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Xie XZ, Zuo L, Huang W, Fan QM, Weng YY, Yao WD, Jiang JL, Jin JQ. FDX1 as a novel biomarker and treatment target for stomach adenocarcinoma. World J Gastrointest Surg 2024; 16:1803-1824. [DOI: 10.4240/wjgs.v16.i6.1803] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/21/2024] [Revised: 04/25/2024] [Accepted: 04/28/2024] [Indexed: 06/27/2024] Open
Abstract
BACKGROUND Stomach adenocarcinoma (STAD) is one of the main reasons for cancer-related deaths worldwide. This investigation aimed to define the connection between STAD and Cuproptosis-related genes (CRGs). Cuproptosis is a newly identified form of mitochondrial cell death triggered by copper.
AIM To explore the identification of potential biomarkers for STAD disease based on cuproptosis.
METHODS A predictive model using Gene Ontology (GO), Least Absolute Shrinkage and Selection Operator (LASSO), Kyoto Encyclopedia of Genes and Genomes (KEGG), Gene Set Variation Analysis (GSVA), and Gene Set Enrichment Analysis analyzed gene interconnections, focusing on 3 copper-related genes and their expression in The Cancer Genome Atlas-STAD. Networks for mRNA-miRNA and mRNA-transcription factor interactions were constructed. The prognostic significance of CRG scores was evaluated using time-receiver operating characteristic, Kaplan-Meier curves, and COX regression analysis. Validation was conducted with datasets GSE26942, GSE54129, and GSE66229. Expression of copper-related differentially expressed genes was also analyzed in various human tissues and gastric cancer subpopulations using the human protein atlas.
RESULTS Three significant genes (FDX1, LIAS, MTF1) were identified and selected via LASSO analysis to predict and classify individuals with STAD into high and low CRG score subgroups. These genes were down-regulated in both risk categories. GO and KEGG analyses highlighted their involvement mainly in the electron transport chain. After validating their differential expression, FDX1 emerged as the most accurate diagnostic marker for gastric cancer. Additionally, the RCircos package localized FDX1 on chromosome 11.
CONCLUSION Our study revealed that FDX1 could be a potential biomarker and treatment target for gastric malignancy, providing new ideas for further scientific research.
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Affiliation(s)
- Xian-Ze Xie
- Department of Pharmacy, The First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Chinese Medicine), Hangzhou 310018, Zhejiang Province, China
| | - Lei Zuo
- Anhui Province Huainan City Shou County Agricultural Machinery Affairs Management Center, Huainan 232200, Anhui Province, China
| | - Wei Huang
- Department of Pharmacy, The First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Chinese Medicine), Hangzhou 310018, Zhejiang Province, China
| | - Qiao-Mei Fan
- Department of Pharmacy, The First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Chinese Medicine), Hangzhou 310018, Zhejiang Province, China
| | - Ya-Yun Weng
- Department of Pharmacy, The First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Chinese Medicine), Hangzhou 310018, Zhejiang Province, China
| | - Wen-Dong Yao
- Department of Pharmacy, The First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Chinese Medicine), Hangzhou 310018, Zhejiang Province, China
| | - Jia-Li Jiang
- Department of Pharmacy, The First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Chinese Medicine), Hangzhou 310018, Zhejiang Province, China
| | - Jia-Qi Jin
- Department of Pharmacy, The First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Chinese Medicine), Hangzhou 310018, Zhejiang Province, China
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Vijayakumar S, DiGuiseppi JA, Dabestani PJ, Ryan WG, Quevedo RV, Li Y, Diers J, Tu S, Fleegel J, Nguyen C, Rhoda LM, Imami AS, Hamoud ARA, Lovas S, McCullumsmith RE, Zallocchi M, Zuo J. In silico transcriptome screens identify epidermal growth factor receptor inhibitors as therapeutics for noise-induced hearing loss. SCIENCE ADVANCES 2024; 10:eadk2299. [PMID: 38896614 PMCID: PMC11186505 DOI: 10.1126/sciadv.adk2299] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/09/2023] [Accepted: 05/14/2024] [Indexed: 06/21/2024]
Abstract
Noise-induced hearing loss (NIHL) is a common sensorineural hearing impairment that lacks U.S. Food and Drug Administration-approved drugs. To fill the gap in effective screening models, we used an in silico transcriptome-based drug screening approach, identifying 22 biological pathways and 64 potential small molecule treatments for NIHL. Two of these, afatinib and zorifertinib [epidermal growth factor receptor (EGFR) inhibitors], showed efficacy in zebrafish and mouse models. Further tests with EGFR knockout mice and EGF-morpholino zebrafish confirmed their protective role against NIHL. Molecular studies in mice highlighted EGFR's crucial involvement in NIHL and the protective effect of zorifertinib. When given orally, zorifertinib was found in the perilymph with favorable pharmacokinetics. In addition, zorifertinib combined with AZD5438 (a cyclin-dependent kinase 2 inhibitor) synergistically prevented NIHL in zebrafish. Our results underscore the potential for in silico transcriptome-based drug screening in diseases lacking efficient models and suggest EGFR inhibitors as potential treatments for NIHL, meriting clinical trials.
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Affiliation(s)
- Sarath Vijayakumar
- Department of Biomedical Sciences, School of Medicine, Creighton University, Omaha, NE 68178, USA
| | - Joseph A. DiGuiseppi
- Department of Biomedical Sciences, School of Medicine, Creighton University, Omaha, NE 68178, USA
| | - Parinaz Jila Dabestani
- Department of Biomedical Sciences, School of Medicine, Creighton University, Omaha, NE 68178, USA
| | - William G. Ryan
- Department of Neurosciences, University of Toledo, Toledo, OH 43614, USA.
| | - Rene Vielman Quevedo
- Department of Biomedical Sciences, School of Medicine, Creighton University, Omaha, NE 68178, USA
| | - Yuju Li
- Department of Biomedical Sciences, School of Medicine, Creighton University, Omaha, NE 68178, USA
| | - Jack Diers
- Department of Biomedical Sciences, School of Medicine, Creighton University, Omaha, NE 68178, USA
| | - Shu Tu
- Department of Biomedical Sciences, School of Medicine, Creighton University, Omaha, NE 68178, USA
| | - Jonathan Fleegel
- Department of Biomedical Sciences, School of Medicine, Creighton University, Omaha, NE 68178, USA
| | - Cassidy Nguyen
- Department of Biomedical Sciences, School of Medicine, Creighton University, Omaha, NE 68178, USA
| | - Lauren M. Rhoda
- Department of Biomedical Sciences, School of Medicine, Creighton University, Omaha, NE 68178, USA
| | - Ali Sajid Imami
- Department of Neurosciences, University of Toledo, Toledo, OH 43614, USA.
| | | | - Sándor Lovas
- Department of Biomedical Sciences, School of Medicine, Creighton University, Omaha, NE 68178, USA
| | - Robert E. McCullumsmith
- Department of Neurosciences, University of Toledo, Toledo, OH 43614, USA.
- Neurosciences Institute, ProMedica, Toledo, OH 43606, USA
| | - Marisa Zallocchi
- Department of Biomedical Sciences, School of Medicine, Creighton University, Omaha, NE 68178, USA
| | - Jian Zuo
- Department of Biomedical Sciences, School of Medicine, Creighton University, Omaha, NE 68178, USA
- Ting Therapeutics, University of California San Diego, 9310 Athena Circle, San Diego, CA 92037, USA
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Xia Y, Sun M, Huang H, Jin WL. Drug repurposing for cancer therapy. Signal Transduct Target Ther 2024; 9:92. [PMID: 38637540 PMCID: PMC11026526 DOI: 10.1038/s41392-024-01808-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2023] [Revised: 03/05/2024] [Accepted: 03/19/2024] [Indexed: 04/20/2024] Open
Abstract
Cancer, a complex and multifactorial disease, presents a significant challenge to global health. Despite significant advances in surgical, radiotherapeutic and immunological approaches, which have improved cancer treatment outcomes, drug therapy continues to serve as a key therapeutic strategy. However, the clinical efficacy of drug therapy is often constrained by drug resistance and severe toxic side effects, and thus there remains a critical need to develop novel cancer therapeutics. One promising strategy that has received widespread attention in recent years is drug repurposing: the identification of new applications for existing, clinically approved drugs. Drug repurposing possesses several inherent advantages in the context of cancer treatment since repurposed drugs are typically cost-effective, proven to be safe, and can significantly expedite the drug development process due to their already established safety profiles. In light of this, the present review offers a comprehensive overview of the various methods employed in drug repurposing, specifically focusing on the repurposing of drugs to treat cancer. We describe the antitumor properties of candidate drugs, and discuss in detail how they target both the hallmarks of cancer in tumor cells and the surrounding tumor microenvironment. In addition, we examine the innovative strategy of integrating drug repurposing with nanotechnology to enhance topical drug delivery. We also emphasize the critical role that repurposed drugs can play when used as part of a combination therapy regimen. To conclude, we outline the challenges associated with repurposing drugs and consider the future prospects of these repurposed drugs transitioning into clinical application.
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Affiliation(s)
- Ying Xia
- Center for Clinical Laboratories, The Affiliated Hospital of Guizhou Medical University, Guiyang, 550004, PR China
- The First Affiliated Hospital of Guizhou University of Traditional Chinese Medicine, Guiyang, 550001, PR China
- School of Clinical Laboratory Science, Guizhou Medical University, Guiyang, 550004, PR China
- Division of Gastroenterology and Hepatology, Department of Medicine and, Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, 21287, USA
| | - Ming Sun
- Center for Clinical Laboratories, The Affiliated Hospital of Guizhou Medical University, Guiyang, 550004, PR China
- School of Clinical Laboratory Science, Guizhou Medical University, Guiyang, 550004, PR China
| | - Hai Huang
- Center for Clinical Laboratories, The Affiliated Hospital of Guizhou Medical University, Guiyang, 550004, PR China.
- School of Clinical Laboratory Science, Guizhou Medical University, Guiyang, 550004, PR China.
| | - Wei-Lin Jin
- Institute of Cancer Neuroscience, Medical Frontier Innovation Research Center, The First Hospital of Lanzhou University, The First Clinical Medical College of Lanzhou University, Lanzhou, 730000, PR China.
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Lv M, Li X, Yin Z, Yang H, Zhou B. Comprehensive analysis and validation reveal DEPDC1 as a potential diagnostic biomarker associated with tumor immunity in non-small-cell lung cancer. PLoS One 2024; 19:e0294227. [PMID: 38564630 PMCID: PMC10986975 DOI: 10.1371/journal.pone.0294227] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2023] [Accepted: 10/20/2023] [Indexed: 04/04/2024] Open
Abstract
Current evidence suggests that DEP domain containing 1 (DEPDC1) has an important effect on non-small-cell lung cancer (NSCLC). However, the diagnostic value and the regulatory function within NSCLC are largely unclear. This work utilized publicly available databases and in vitro experiments for exploring, DEPDC1 expression, clinical features, diagnostic significance and latent molecular mechanism within NSCLC. According to our results, DEPDC1 was remarkably upregulated in the tissues of NSCLC patients compared with non-carcinoma tissues, linked with gender, stage, T classification and N classification based on TCGA data and associated with smoking status and stage according to GEO datasets. Meanwhile, the summary receiver operating characteristic (sROC) curve analysis result showed that DEPDC1 had a high diagnostic value in NSCLC (AUC = 0.96, 95% CI: 0.94-0.98; diagnostic odds ratio = 99.08, 95%CI: 31.91-307.65; sensitivity = 0.89, 95%CI: 0.81-0.94; specificity = 0.92, 95%CI: 0.86-0.96; positive predictive value = 0.94, 95%CI: 0.89-0.98; negative predictive value = 0.78, 95%CI: 0.67-0.90; positive likelihood ratio = 11.77, 95%CI: 6.11-22.68; and negative likelihood ratio = 0.12, 95%CI: 0.06-0.22). Subsequently, quantitative real-time PCR (qRT-PCR) and western blotting indicated that DEPDC1 was high expressed in NSCLC cells. According to the in vitro MTS and apoptotic assays, downregulated DEPDC1 expression targeting P53 signaling pathway inhibited the proliferation of NSCLC cells while promoting apoptosis of NSCLC cells. Moreover, DEPDC1 was significantly correlated with immune cell infiltrating levels in NSCLC based on TCGA data, which were primarily associated with T cells CD4 memory activated, macrophages M1, B cells memory, mast cells resting, T cells regulatory, monocytes, and T cells CD4 memory resting. Compared with the group with high expression of DEPDC1, the group with low expression level had higher scores for immune checkpoint inhibitors (ICIs) treatment. GSEA confirmed that DEPDC1 was involved in gene expression and tumor-related signaling pathways. Finally, DEPDC1 and its associated immune-related genes were shown to be enriched in 'receptor ligand activity', 'external side of plasma membrane', 'regulation of innate immune response', and 'Epstein-Barr virus infection' pathways. The present study demonstrates that DEPDC1 may contribute to NSCLC tumorigenesis and can be applied as the biomarker for diagnosis and immunology.
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Affiliation(s)
- Meiwen Lv
- Department of Clinical Epidemiology, The First Hospital of China Medical University, Heping District, Shenyang, China
| | - Xuelian Li
- Department of Epidemiology, School of Public Health of China Medical University, Shenyang, China
| | - Zhihua Yin
- Department of Epidemiology, School of Public Health of China Medical University, Shenyang, China
| | - He Yang
- Department of Clinical Epidemiology, The First Hospital of China Medical University, Heping District, Shenyang, China
| | - Baosen Zhou
- Department of Clinical Epidemiology, The First Hospital of China Medical University, Heping District, Shenyang, China
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Ma WQ, Miao MC, Ding PA, Tan BB, Liu WB, Guo S, Er LM, Zhang ZD, Zhao Q. CALD1 facilitates epithelial-mesenchymal transition progression in gastric cancer cells by modulating the PI3K-Akt pathway. World J Gastrointest Oncol 2024; 16:1029-1045. [PMID: 38577446 PMCID: PMC10989365 DOI: 10.4251/wjgo.v16.i3.1029] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/22/2023] [Revised: 12/21/2023] [Accepted: 01/04/2024] [Indexed: 03/12/2024] Open
Abstract
BACKGROUND CALD1 has been discovered to be abnormally expressed in a variety of malignant tumors, including gastric cancer (GC), and is associated with tumor progression and immune infiltration; however, the roles and mechanisms of CALD1 in epithelial-mesenchymal transition (EMT) in GC are unknown. AIM To investigate the role and mechanism of CALD1 in GC progression, invasion, and migration. METHODS In this study, the relationship between CALD1 and GC, as well as the possible network regulatory mechanisms of CALD1, was investigated by bioinformatics and validated by experiments. CALD1-siRNA was synthesized and used to transfect GC cells. Cell activity was measured using the CCK-8 method, cell migration and invasive ability were measured using wound healing assay and Transwell assay, and the expression levels of relevant genes and proteins in each group of cells were measured using qRT-PCR and Western blot. A GC cell xenograft model was established to verify the results of in vitro experiments. RESULTS Bioinformatics results showed that CALD1 was highly expressed in GC tissues, and CALD1 was significantly higher in EMT-type GC tissues than in tissues of other types of GC. The prognosis of patients with high expression of CALD1 was worse than that of patients with low expression, and a prognostic model was constructed and evaluated. The experimental results were consistent with the results of the bioinformatics analysis. The expression level of CALD1 in GC cell lines was all higher than that in gastric epithelial cell line GES-1, with the strongest expression found in AGS and MKN45 cells. Cell activity was significantly reduced after CALD1-siRNA transfection of AGS and MKN45 cells. The ability of AGS and MKN45 cells to migrate and invade was reduced after CALD1-siRNA transfection, and the related mRNA and protein expression was altered. According to bioinformatics findings in GC samples, the CALD1 gene was significantly associated with the expression of members of the PI3K-AKT-mTOR signaling pathway as well as the EMT signaling pathway, and was closely related to the PI3K-Akt signaling pathway. Experimental validation revealed that upregulation of CALD1 increased the expression of PI3K, p-AKT, and p-mTOR, members of the PI3K-Akt pathway,while decreasing the expression of PTEN; PI3K-Akt inhibitor treatment decreased the expression of PI3K, p-AKT, and p-mTOR in cells overexpressing CALD1 (still higher than that in the normal group), but increased the expression of PTEN (still lower than that in the normal group). CCK-8 results revealed that the effect of CALD1 on tumor cell activity was decreased by the addition of the inhibitor. Scratch and Transwell experiments showed that the effect of CALD1 on tumor cell migration and invasion was weakened by the addition of the PI3K-Akt inhibitor. The mRNA and protein levels of EMT-related genes in AGS and MKN45 cells were greatly altered by the overexpression of CALD1, whereas the effect of overexpression of CALD1 was significantly weakened by the addition of the PI3K-Akt inhibitor. Animal experiments showed that tumour growth was slow after inhibition of CALD1, and the expression of some PI3K-Akt and EMT pathway proteins was altered. CONCLUSION Increased expression of CALD1 is a key factor in the progression, invasion, and metastasis of GC, which may be associated with regulating the PI3K-Akt pathway to promote EMT.
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Affiliation(s)
- Wen-Qian Ma
- Department of Endoscopy, The Fourth Hospital of Hebei Medical University, Shijiazhuang 050011, Hebei Province, China
- Hebei Key Laboratory of Precision Diagnosis and Comprehensive Treatment of Gastric Cancer, Shijiazhuang 050011, Hebei Province, China
| | - Ming-Chang Miao
- Department of Radiotherapy, The Fourth Hospital of Hebei Medical University, Shijiazhuang 050011, Hebei Province, China
| | - Ping-An Ding
- Hebei Key Laboratory of Precision Diagnosis and Comprehensive Treatment of Gastric Cancer, Shijiazhuang 050011, Hebei Province, China
- The Third Department of Surgery, The Fourth Hospital of Hebei Medical University, Shijiazhuang 050011, Hebei Province, China
| | - Bi-Bo Tan
- Hebei Key Laboratory of Precision Diagnosis and Comprehensive Treatment of Gastric Cancer, Shijiazhuang 050011, Hebei Province, China
- The Third Department of Surgery, The Fourth Hospital of Hebei Medical University, Shijiazhuang 050011, Hebei Province, China
| | - Wen-Bo Liu
- Hebei Key Laboratory of Precision Diagnosis and Comprehensive Treatment of Gastric Cancer, Shijiazhuang 050011, Hebei Province, China
- The Third Department of Surgery, The Fourth Hospital of Hebei Medical University, Shijiazhuang 050011, Hebei Province, China
| | - Shuo Guo
- Department of Endoscopy, The Fourth Hospital of Hebei Medical University, Shijiazhuang 050011, Hebei Province, China
- Hebei Key Laboratory of Precision Diagnosis and Comprehensive Treatment of Gastric Cancer, Shijiazhuang 050011, Hebei Province, China
| | - Li-Mian Er
- Department of Endoscopy, The Fourth Hospital of Hebei Medical University, Shijiazhuang 050011, Hebei Province, China
- Hebei Key Laboratory of Precision Diagnosis and Comprehensive Treatment of Gastric Cancer, Shijiazhuang 050011, Hebei Province, China
| | - Zhi-Dong Zhang
- Hebei Key Laboratory of Precision Diagnosis and Comprehensive Treatment of Gastric Cancer, Shijiazhuang 050011, Hebei Province, China
- The Third Department of Surgery, The Fourth Hospital of Hebei Medical University, Shijiazhuang 050011, Hebei Province, China
| | - Qun Zhao
- Hebei Key Laboratory of Precision Diagnosis and Comprehensive Treatment of Gastric Cancer, Shijiazhuang 050011, Hebei Province, China
- The Third Department of Surgery, The Fourth Hospital of Hebei Medical University, Shijiazhuang 050011, Hebei Province, China
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Chen J, Liang H, Wu Y, Li C. Phosphoproteomics changes due to allograft-induced stress responses of Pinctada fucata martensii. COMPARATIVE BIOCHEMISTRY AND PHYSIOLOGY. PART D, GENOMICS & PROTEOMICS 2024; 49:101153. [PMID: 37956605 DOI: 10.1016/j.cbd.2023.101153] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/29/2023] [Revised: 11/01/2023] [Accepted: 11/03/2023] [Indexed: 11/15/2023]
Abstract
Protein phosphorylation modifications are post-translational modifications (PTMs) that play important roles in signal transduction and immune regulation. Implanting a spherical nucleus into a recipient shellfish is critical in marine pearl aquaculture. Protein phosphorylation may be important in the immune responses of Pinctada fucata martensii after nucleus implantation, but their involvement in regulation remains unclear. Here, phosphoproteomics of P. f. martensii gill tissues was conducted 12 h after nuclear implantation using label-free data-independent acquisition (DIA) with LC-MS/MS. Among the 4024 phosphorylated peptides with quantitative information, 181 were up-regulated and 148 were down-regulated. Functional enrichment analysis of these differentially expressed phosphorylated proteins (DEPPs) revealed significant enrichment in functions related to membrane trafficking, exosomes, cytoskeleton, and signal transduction mechanisms. Further, 16 conserved motifs were identified among the DEPPs, including the RSphP, SphP, RSphA, RSphE, PTphP, and ATphP motifs that were significantly conserved, and which may be related to specific kinase recognition. Parallel response monitoring (PRM) analysis validated the abundances of 12 DEPPs from the proteomics, indicating that the phosphoproteomics analyses were robust. 12 DEPPs were selected from the proteomics results through Quantitative real-time PCR (qPCR) technology, and verification analysis was conducted at the gene level. The study suggests that kinases such as MAPKs, Akt, and CK2 may regulate the phosphorylation of related proteins following nuclear implantation. Furthermore, the important signaling pathways of Rap 1, IL-17A, and NF-κB, which are influenced by phosphorylated or dephosphorylated proteins, are found to be involved in this response. Overall, this study revealed the protein phosphorylation responses after nucleus implantation in P. f. martensii, helping to elucidate the characteristics and mechanisms of immune regulation responses in P. f. martensii, in addition to promoting a further understanding of protein phosphorylation modification functions in P. f. martensii.
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Affiliation(s)
- Jie Chen
- Fisheries College, Guangdong Ocean University, Zhanjiang 524088, China
| | - Haiying Liang
- Fisheries College, Guangdong Ocean University, Zhanjiang 524088, China; Guangdong Provincial Key Laboratory of Aquatic Animal Disease Control and Healthy Culture, Zhanjiang 524088, China.
| | - Yifan Wu
- Fisheries College, Guangdong Ocean University, Zhanjiang 524088, China
| | - Chaojie Li
- Fisheries College, Guangdong Ocean University, Zhanjiang 524088, China
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Zhang Y, Guo S, Mao T, Guo J, Zhang Q, Tian Z, Li X. Tumor-Derived Exosomal LINC01480 Upregulates VCAM1 Expression by Acting as a Competitive Endogenous RNA of miR-204-5p to Promote Gastric Cancer Progression. ACS Biomater Sci Eng 2024; 10:550-562. [PMID: 38133901 DOI: 10.1021/acsbiomaterials.3c00394] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2023]
Abstract
Exosomes are a type of cell-derived vesicles that range in size from 30 to 100 nm. They are widely present in various organisms and participate in diverse biological processes, playing crucial roles in tumorigenesis and progression. This study aimed to investigate whether LINC01480 in tumor-derived exosomes is involved in the molecular mechanism of gastric cancer by competitively upregulating the VCAM1 expression through binding miR-204-5p. The study analyzed transcriptome data related to gastric cancer from the cancer genome atlas database and constructed a risk-scoring model for epithelial-mesenchymal transition (EMT)-related lncRNAs to identify eight EMT-related lncRNAs associated with prognosis. EMT-related mRNAs positively correlated with LINC01480 were screened in the ExoRBase database. In vitro cell experiments showed that exosomal LINC01480 can promote the proliferation, migration, invasion, and EMT of gastric cancer cells by upregulating VCAM1 expression through competitive binding with miR-204-5p. In vivo experiments on nude mice showed that exosomal LINC01480 promotes the development of gastric cancer. These results suggest that exosomal LINC01480 could be a potential therapeutic target for gastric cancer.
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Affiliation(s)
- Yu Zhang
- Department of Gastroenterology, The Affiliated Hospital of Qingdao University, Qingdao 266000, P. R. China
| | - Shan Guo
- Department of Gastroenterology, The Affiliated Hospital of Qingdao University, Qingdao 266000, P. R. China
| | - Tao Mao
- Department of Gastroenterology, The Affiliated Hospital of Qingdao University, Qingdao 266000, P. R. China
| | - Jing Guo
- Department of Gastroenterology, The Affiliated Hospital of Qingdao University, Qingdao 266000, P. R. China
| | - Qi Zhang
- Department of Gastroenterology, The Affiliated Hospital of Qingdao University, Qingdao 266000, P. R. China
| | - Zibin Tian
- Department of Gastroenterology, The Affiliated Hospital of Qingdao University, Qingdao 266000, P. R. China
| | - Xiaoyu Li
- Department of Gastroenterology, The Affiliated Hospital of Qingdao University, Qingdao 266000, P. R. China
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Qiao X, Chen Y, Wang Z, Peng N, Niu W, Hou S, Wu J, Ji Y, Niu C, Cheng C. GTF2E2 downregulated by miR-340-5p inhibits the malignant progression of glioblastoma. Cancer Gene Ther 2023; 30:1702-1714. [PMID: 37845349 DOI: 10.1038/s41417-023-00676-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2023] [Revised: 09/08/2023] [Accepted: 09/29/2023] [Indexed: 10/18/2023]
Abstract
Glioblastoma is the most common malignant tumor in the central nervous system. The general transcription factor IIE subunit beta (GTF2E2) is crucial for physiological and pathological functions, but its roles in the malignant biological function of glioma remain ambiguous. CCK-8, colony formation assays, TUNEL assays, cell migration assays, wound-healing assays, and xenograft model were established to investigate the biological functions of GTF2E2 both in vitro and in vivo. GTF2E2 was overexpressed in glioma and was associated with poor prognosis of glioma patients. Biological functions of GTF2E2 were investigated both in vitro and in vi0vo by multiple experiments. Moreover, we explored the possible mechanisms of GTF2E2. In our results, we demonstrated that GTF2E2 could be regulated by miR-340-5p directly or indirectly. CCND1 was transcriptionally affected by GTF2E2 and glioma progression was then regulated. Our data presented the overexpression of GTF2E2 in glioma and indicated the association between GTF2E2 and glioma prognosis. GTF2E2 was found to be regulated by miR-340-5p and thus affect downstream gene expressions and glioma progression. Our results indicate that GTF2E2 might be a potential target in the diagnosis and treatments of glioblastoma.
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Affiliation(s)
- Xiaolong Qiao
- Anhui University of Science and Technology, 232001, Huainan, Anhui, China
- Department of Neurosurgery, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, 230001, Hefei, Anhui, China
| | - Yinan Chen
- Department of Neurosurgery, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, 230001, Hefei, Anhui, China
| | - Zixuan Wang
- Dalian Medical University, 116000, Dalian, Liaoning, China
| | - Nan Peng
- Department of Neurosurgery, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, 230001, Hefei, Anhui, China
| | - Wanxiang Niu
- Department of Neurosurgery, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, 230001, Hefei, Anhui, China
| | - Shiqiang Hou
- Department of Neurosurgery, The Affiliated Chuzhou Hospital of Anhui Medical University, The First People's Hospital of Chuzhou, 239000, Chuzhou, Anhui, China
| | - Jiaying Wu
- Bengbu Medical College, 233000, Bengbu, Anhui, China
| | - Ying Ji
- Department of Neurosurgery, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, 230001, Hefei, Anhui, China.
| | - Chaoshi Niu
- Department of Neurosurgery, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, 230001, Hefei, Anhui, China.
| | - Chuandong Cheng
- Anhui University of Science and Technology, 232001, Huainan, Anhui, China.
- Department of Neurosurgery, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, 230001, Hefei, Anhui, China.
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Deng H, Gao J, Cao B, Qiu Z, Li T, Zhao R, Li H, Wei B. LncRNA CCAT2 promotes malignant progression of metastatic gastric cancer through regulating CD44 alternative splicing. Cell Oncol (Dordr) 2023; 46:1675-1690. [PMID: 37354353 DOI: 10.1007/s13402-023-00835-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/30/2023] [Indexed: 06/26/2023] Open
Abstract
OBJECTIVE Gastric cancer (GC) is one of the most malignant tumors worldwide. Thus, it is necessary to explore the underlying mechanisms of GC progression and develop novel therapeutic regimens. Long non-coding RNAs (lncRNAs) have been demonstrated to be abnormally expressed and regulate the malignant behaviors of cancer cells. Our previous research demonstrated that lncRNA colon cancer-associated transcript 2 (CCAT2) has potential value for GC diagnosis and discrimination. However, the functional mechanisms of lncRNA CCAT2 in GC development remain to be explored. METHODS GC and normal adjacent tissues were collected to detect the expression of lncRNA CCAT2, ESRP1 and CD44 in clinical specimens and their clinical significance for GC patients. Cell counting kit-8, wound healing and transwell assays were conducted to investigate the malignant behaviors in vitro. The generation of nude mouse xenografts by subcutaneous, intraperitoneal and tail vein injection was performed to examine GC growth and metastasis in vivo. Co-immunoprecipitation, RNA-binding protein pull-down assay and fluorescence in situ hybridization were performed to reveal the binding relationships between ESRP1 and CD44. RESULTS In the present study, lncRNA CCAT2 was overexpressed in GC tissues compared to adjacent normal tissues and correlated with short survival time of patients. lncRNA CCAT2 promoted the proliferation, migration and invasion of GC cells. Its overexpression modulates alternative splicing of Cluster of differentiation 44 (CD44) variants and facilitates the conversion from the standard form to variable CD44 isoform 6 (CD44v6). Mechanistically, lncRNA CCAT2 upregulated CD44v6 expression by binding to epithelial splicing regulatory protein 1 (ESRP1), which subsequently mediates CD44 alternative splicing. The oncogenic role of the lncRNA CCAT2/ESRP1/CD44 axis in the promotion of malignant behaviors was verified by both in vivo and in vitro experiments. CONCLUSIONS Our findings identified a novel mechanism by which lncRNA CCAT2, as a type of protein-binding RNA, regulates alternative splicing of CD44 and promotes GC progression. This axis may become an effective target for clinical diagnosis and treatment.
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Affiliation(s)
- Huan Deng
- Department of Gastrointestinal Surgery, Peking University First Hospital, Beijing, 100034, China
- Department of General Surgery, First Medical Center, Chinese PLA General Hospital, 28 Fuxing Rd, Beijing, 100853, China
- Medical School of Chinese PLA, Beijing, 100853, China
| | - Jingwang Gao
- Department of General Surgery, First Medical Center, Chinese PLA General Hospital, 28 Fuxing Rd, Beijing, 100853, China
- Medical School of Chinese PLA, Beijing, 100853, China
| | - Bo Cao
- Department of General Surgery, First Medical Center, Chinese PLA General Hospital, 28 Fuxing Rd, Beijing, 100853, China
- Medical School of Chinese PLA, Beijing, 100853, China
| | - Ziyu Qiu
- Health Service Department of the Guard Bureau of the General Office of the Central Committee of the Communist Party of China, Beijing, 100091, China
| | - Tian Li
- School of Basic Medicine, The Fourth Military Medical University, Xi'an, 710021, China
| | - Ruiyang Zhao
- Department of General Surgery, First Medical Center, Chinese PLA General Hospital, 28 Fuxing Rd, Beijing, 100853, China
- Medical School of Chinese PLA, Beijing, 100853, China
| | - Hanghang Li
- Department of General Surgery, First Medical Center, Chinese PLA General Hospital, 28 Fuxing Rd, Beijing, 100853, China
- Medical School of Chinese PLA, Beijing, 100853, China
| | - Bo Wei
- Department of General Surgery, First Medical Center, Chinese PLA General Hospital, 28 Fuxing Rd, Beijing, 100853, China.
- Medical School of Chinese PLA, Beijing, 100853, China.
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10
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Shaemi F, Nejati M, Sarrafnia H, Mahabady MK, Tamtaji Z, Taheri AT, Hamblin MR, Zolfaghari MR, Heydari A, Mirzaei H. Expression of selected long non-coding RNAs in gastric cancer cells treated with coumarin: Possible mechanisms for anti-cancer activity. Pathol Res Pract 2023; 252:154914. [PMID: 37992506 DOI: 10.1016/j.prp.2023.154914] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/10/2023] [Revised: 10/26/2023] [Accepted: 10/26/2023] [Indexed: 11/24/2023]
Abstract
Long non-coding RNAs (lncRNAs) can be utilized as prognostic indicators of gastric cancer since they can affect several cancer-related processes. Coumarin is a natural product with some useful anti-cancer properties. Here, we measured the expression of selected lncRNAs (RuPAR, SNHG6, CASC11, and their targets, miR-340-5p, p21, E-cadherin, and CDK1) in AGS gastric cancer cells treated with coumarin. MTT test has been utilized for assessing the AGS cells' cell viability after exposure to coumarin. The expression of the lncRNAs (RuPAR, SNHG6, and CASC11) and miR-340-5p was evaluated via qRT-PCR. Western blot analysis has been utilized to determine changes in p21, E-cadherin, and CDK1 expression. Coumarin decreased AGS viability in a dose-dependent manner. The coumarin treated cells had lower levels of the mRNAs known to be targets of lncRNAs SNHG6 and CASC11 compared to control. Additionally, the coumarin group had increased levels of lncRNA RuPAR expression when compared with the control group. Some lncRNA targets, including p21, E-cadherin, and CDK1, showed lower expression in the coumarin group compared to the control by Western blotting. Coumarin could be a promising pharmacological candidate to be included in gastric cancer treatment regimens because it modulates lncRNAs and their targets.
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Affiliation(s)
- Fatemeh Shaemi
- Department of Genetics, Faculty of Basic Science, Qom Branch, Islamic Azad University, Qom, Iran
| | - Majid Nejati
- Anatomical Sciences Research Center, Institute for Basic Sciences, Kashan University of Medical Sciences, Kashan, Iran
| | - Haleh Sarrafnia
- Faculty of Biological Sciences, Islamic Azad University, Tehran-North Branch, Tehran, Iran
| | - Mahmood Khaksary Mahabady
- Anatomical Sciences Research Center, Institute for Basic Sciences, Kashan University of Medical Sciences, Kashan, Iran
| | - Zeinab Tamtaji
- Student Research Committee, Kashan University of Medical Sciences, Kashan, Iran
| | - Abdolkarim Talebi Taheri
- Student Research Committee, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Michael R Hamblin
- Laser Research Centre, Faculty of Health Science, University of Johannesburg, Doornfontein 2028, South Africa
| | - Mohammad Reza Zolfaghari
- Department of Microbiology, Faculty of Basic Science, Qom Branch, Islamic Azad University, Qom, Iran.
| | - Azhdar Heydari
- Physiology Research Center, Institute for Basic Sciences, Kashan University of Medical Sciences, Kashan, Iran; Department of Physiology, School of Medicine, Kashan University of Medical Sciences, Kashan, Iran.
| | - Hamed Mirzaei
- Research Center for Biochemistry and Nutrition in Metabolic Diseases, Institute for Basic Sciences, Kashan University of Medical Sciences, Kashan, Iran; Research Center for Biochemistry and Nutrition in Metabolic Diseases, Institute for Basic Sciences, Kashan University of Medical Sciences, Kashan, Iran.
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11
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Sahib AS, Fawzi A, Zabibah RS, Koka NA, Khudair SA, Muhammad FA, Hamad DA. miRNA/epithelial-mesenchymal axis (EMT) axis as a key player in cancer progression and metastasis: A focus on gastric and bladder cancers. Cell Signal 2023; 112:110881. [PMID: 37666286 DOI: 10.1016/j.cellsig.2023.110881] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2023] [Revised: 08/30/2023] [Accepted: 09/01/2023] [Indexed: 09/06/2023]
Abstract
The metastasis a major hallmark of tumors that its significant is not only related to the basic research, but clinical investigations have revealed that majority of cancer deaths are due to the metastasis. The metastasis of tumor cells is significantly increased due to EMT mechanism and therefore, inhibition of EMT can reduce biological behaviors of tumor cells and improve the survival rate of patients. One of the gaps related to cancer metastasis is lack of specific focus on the EMT regulation in certain types of tumor cells. The gastric and bladder cancers are considered as two main reasons of death among patients in clinical level. Herein, the role of EMT in regulation of their progression is evaluated with a focus on the function of miRNAs. The inhibition/induction of EMT in these cancers and their ability in modulation of EMT-related factors including ZEB1/2 proteins, TGF-β, Snail and cadherin proteins are discussed. Moreover, lncRNAs and circRNAs in crosstalk of miRNA/EMT regulation in these tumors are discussed and final impact on cancer metastasis and response of tumor cells to the chemotherapy is evaluated. Moreover, the impact of miRNAs transferred by exosomes in regulation of EMT in these cancers are discussed.
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Affiliation(s)
- Ameer S Sahib
- Department of Pharmacy, Al- Mustaqbal University College, 51001 Hilla, Iraq
| | - Amjid Fawzi
- Medical Technical College, Al-Farahidi University, Iraq
| | - Rahman S Zabibah
- Medical Laboratory Technology Department, College of Medical Technology, The Islamic University, Najaf, Iraq
| | - Nisar Ahmad Koka
- Department of English, Faculty of Languages and Translation, King Khalid University, Abha, Kingdom of Saudi Arabia.
| | | | | | - Doaa A Hamad
- Nursing Department, Hilla University College, Babylon, Iraq
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12
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Rajan JR, McDonald S, Bjourson AJ, Zhang SD, Gibson DS. An AI Approach to Identifying Novel Therapeutics for Rheumatoid Arthritis. J Pers Med 2023; 13:1633. [PMID: 38138860 PMCID: PMC10744895 DOI: 10.3390/jpm13121633] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2023] [Revised: 11/11/2023] [Accepted: 11/20/2023] [Indexed: 12/24/2023] Open
Abstract
Rheumatoid arthritis (RA) is a chronic autoimmune disorder that has a significant impact on quality of life and work capacity. Treatment of RA aims to control inflammation and alleviate pain; however, achieving remission with minimal toxicity is frequently not possible with the current suite of drugs. This review aims to summarise current treatment practices and highlight the urgent need for alternative pharmacogenomic approaches for novel drug discovery. These approaches can elucidate new relationships between drugs, genes, and diseases to identify additional effective and safe therapeutic options. This review discusses how computational approaches such as connectivity mapping offer the ability to repurpose FDA-approved drugs beyond their original treatment indication. This review also explores the concept of drug sensitisation to predict co-prescribed drugs with synergistic effects that produce enhanced anti-disease efficacy by involving multiple disease pathways. Challenges of this computational approach are discussed, including the availability of suitable high-quality datasets for comprehensive analysis and other data curation issues. The potential benefits include accelerated identification of novel drug combinations and the ability to trial and implement established treatments in a new index disease. This review underlines the huge opportunity to incorporate disease-related data and drug-related data to develop methods and algorithms that have strong potential to determine novel and effective treatment regimens.
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Affiliation(s)
- Jency R. Rajan
- Personalised Medicine Centre, School of Medicine, Ulster University, Londonderry BT47 6SB, UK; (J.R.R.); (A.J.B.); (S.-D.Z.)
| | - Stephen McDonald
- Rheumatology Department, Altnagelvin Hospital, Western Health and Social Care Trust, Londonderry BT47 6SB, UK;
| | - Anthony J. Bjourson
- Personalised Medicine Centre, School of Medicine, Ulster University, Londonderry BT47 6SB, UK; (J.R.R.); (A.J.B.); (S.-D.Z.)
| | - Shu-Dong Zhang
- Personalised Medicine Centre, School of Medicine, Ulster University, Londonderry BT47 6SB, UK; (J.R.R.); (A.J.B.); (S.-D.Z.)
| | - David S. Gibson
- Personalised Medicine Centre, School of Medicine, Ulster University, Londonderry BT47 6SB, UK; (J.R.R.); (A.J.B.); (S.-D.Z.)
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13
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Sha R, Zhang J, Meng F, Zhaori G. Gastric cancer metastasis-related NT5DC2 indicates unfavorable prognosis of patients. Medicine (Baltimore) 2023; 102:e35030. [PMID: 37800836 PMCID: PMC10553061 DOI: 10.1097/md.0000000000035030] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/21/2023] [Accepted: 08/10/2023] [Indexed: 10/07/2023] Open
Abstract
PURPOSE Approximately 80 to 90% of patients with gastric cancer (GC) eventually develop into metastatic GC nowadays,because GC is difficult to be diagnosed at an early stage. GC patients with metastases typically have a poor prognosis. It is necessary to explore a potential prognostic marker in metastatic GC. METHODS All GC data were obtained from The Cancer Genome Atlas and Gene Expression Omnibus databases. The metastasis-related candidate gene and its role in GC were analyzed by comprehensive analysis. RESULTS Totally 1049 metastasis-related genes were identified in GC. Univariate Cox regression analysis screened the top 10 genes (PDHX, SLC43A1, CSAG2, NT5DC2, CSAG1, FMN1, MED1, HIVEP2, FNDC3A, and PPP1R2) that were closely correlated with prognosis of GC patients. Among which, NT5DC2 was screened as the target gene for subsequent study. The NT5DC2 expression were increased in primary GC and metastatic GC samples. Moreover, GC patients with high NT5DC2 expression exhibited shorter overall survival and post progression survival, and the NT5DC2 was metastatic GC patients' independent prognostic factor. Totally 29 pathways were activated in metastatic GC samples with high NT5DC2 expression. Four immune cells' infiltration were significantly different between NT5DC2 high and low expressed metastatic GC patients. NT5DC2 showed significantly negative correlations with 6 types of immune cells' critical marker genes and 5 types of immune cell infiltration. The 10 immune checkpoint expressions were decreased in high NTDC2 expression metastatic GC patients. CONCLUSIONS NT5DC2 plays a prognostic role in metastatic GC. GC patients with high NT5DC2 expression indicates unfavorable prognosis.
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Affiliation(s)
- Rula Sha
- Department of Internal Medicine-Oncology, Inner Mongolia Autonomous Region People’s Hospital, Hohhot, Inner Mongolia, P.R. China
| | - Jiaming Zhang
- Department of Internal Medicine, Inner Mongolia Medical University, Hohhot, Inner Mongolia, P.R. China
| | - Fanjie Meng
- Department of Internal Medicine, Inner Mongolia Medical University, Hohhot, Inner Mongolia, P.R. China
| | - Getu Zhaori
- Department of Abdominal Surgery, The Affiliated People’s Hospital of Inner Mongolia Medical University, Hohhot, Inner Mongolia, P.R. China
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Chen F, Wang L. Long noncoding RNA CASC11 suppresses sorafenib-triggered ferroptosis via stabilizing SLC7A11 mRNA in hepatocellular carcinoma cells. Discov Oncol 2023; 14:145. [PMID: 37552314 PMCID: PMC10409942 DOI: 10.1007/s12672-023-00761-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/27/2023] [Accepted: 07/27/2023] [Indexed: 08/09/2023] Open
Abstract
As a frontline treatment for patients with advanced hepatocellular carcinoma (HCC), sorafenib is an effective drug approved by the Food and Drug Administration (FDA). Ferroptosis, a newly defined programmed cell death process with the hallmark of the accumulation of iron-dependent lipid peroxides, can be induced by sorafenib treatment. Our previous study identified oncogenic roles of long noncoding RNA (lncRNA) Cancer susceptibility candidate 11 (CASC11) in HCC progression. However, the relationship between CASC11 and sorafenib-induced ferroptosis in HCC remains unclear. In the present study, we aim to investigate the role of CASC11 in sorafenib-induced ferroptosis in HCC cell lines and determine the involved molecular mechanisms. Here, we demonstrated that sorafenib decreased CASCL11 expression. Knockdown of CASC11 enhanced sorafenib-induced ferroptosis, while overexpression of CASC11 exerted the opposite effect in HCC cells. Moreover, CASC11 led to the accumulation of intracellular malondialdehyde (MDA), lipid reactive oxygen species (ROS) and Fe2+ while depleting glutathione (GSH), thereby suppressing sorafenib-induced ferroptosis and cell death. Ferrostatin-1 (Ferr-1), a ferroptosis inhibitor, reversed the enhanced anticancer effect of sorafenib caused by the silence of CASC11 in HCC cells. Mechanistically, CASC11 upregulated the expression of solute carrier family 7 member 11 (SLC7A11) which is critical for ferroptosis inhibition. CASC11 associated with and stabilized SLC7A11 mRNA. In summary, our data revealed, for the first time, that CASC11 inhibits the sorafenib-induced ferroptosis in HCC cells via regulating SLC7A11, providing a new basis for clinical therapeutic strategies for patients with HCC.
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Affiliation(s)
- Fei Chen
- Department of Ultrasound, The First Affiliated Hospital of Jinzhou Medical University, Jinzhou, China
| | - Liang Wang
- Department of General Surgery, The First Affiliated Hospital of Jinzhou Medical University, Jinzhou, 121001, Liaoning Province, China.
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15
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Liu N, Zhang C, Zhang L. WTAP-Involved the m6A Modification of lncRNA FAM83H-AS1 Accelerates the Development of Gastric Cancer. Mol Biotechnol 2023:10.1007/s12033-023-00810-2. [PMID: 37477820 DOI: 10.1007/s12033-023-00810-2] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2022] [Accepted: 06/28/2023] [Indexed: 07/22/2023]
Abstract
The long noncoding RNA FAM83H-antisense RNA 1 (FAM83H-AS1) is involved in gastric cancer (GC) development. This study determined whether FAM83H-AS1 was regulated by N6-methyladenosine (m6A) modifications in GC. Real-time quantitative polymerase chain reaction was performed to determine the expression levels of FAM83H-AS1 and Wilms' tumor 1 associated protein (WTAP). The protein content of WTAP was evaluated using western blotting. To assess the m6A alterations in FAM83H-AS1, methylated RNA immunoprecipitation was performed to identify interactions between WTAP and FAM83H-AS1. Functionally, the proliferation, migration, and invasion of GC cells were measured using a Cell Counting Kit-8 and transwell assays, respectively. High expression levels of FAM83H-AS1 and WTAP were detected in GC samples and there was a positive correlation between them. In addition, WTAP mediates FAM83H-AS1 expression in an m6A-dependent manner. Further investigations indicated that WTAP silencing reversed the cancer-promoting role of FAM83H-AS1 overexpression in GC cell migration, proliferation, and invasion. Our results suggest that WTAP-mediated FAM83H-AS1 promotes GC development via m6A modification. Our findings provide new biomarkers for GC diagnosis and targeted therapy. Wilms' tumor 1 associated protein (WTAP) promotes gastric cancer (GC) by accelerating cell proliferation, migration, and invasion of GC cells via the N6-methyladenosine(m6A) modification of long non coding RNA FAM83H-AS1.
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Affiliation(s)
- Nian Liu
- Department of Gastrointestinal Surgery, The Sixth Hospital of Wuhan, Affiliated Hospital of Jianghan University, Hongkong Rd. No. 168, Jianghan District, Wuhan, 430015, Hubei, China
| | - Chao Zhang
- Department of Gastrointestinal Surgery, The Sixth Hospital of Wuhan, Affiliated Hospital of Jianghan University, Hongkong Rd. No. 168, Jianghan District, Wuhan, 430015, Hubei, China
| | - Liang Zhang
- Department of Gastrointestinal Surgery, The Sixth Hospital of Wuhan, Affiliated Hospital of Jianghan University, Hongkong Rd. No. 168, Jianghan District, Wuhan, 430015, Hubei, China.
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Nowak P, Bil-Lula I, Śliwińska-Mossoń M. A Cross-Talk about Radioresistance in Lung Cancer-How to Improve Radiosensitivity According to Chinese Medicine and Medicaments That Commonly Occur in Pharmacies. Int J Mol Sci 2023; 24:11206. [PMID: 37446385 DOI: 10.3390/ijms241311206] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2023] [Revised: 06/21/2023] [Accepted: 06/27/2023] [Indexed: 07/15/2023] Open
Abstract
Lung cancer is one of the most common cancers in the population and is characterized by non-specific symptoms that delay the diagnosis and reduce the effectiveness of oncological treatment. Due to the difficult placement of the tumor, one of the main methods of lung cancer treatment is radiotherapy, which damages the DNA of cancer cells, inducing their apoptosis. However, resistance to ionizing radiation may develop during radiotherapy cycles, leading to an increase in the number of DNA points of control that protect cells from apoptosis. Cancer stem cells are essential for radioresistance, and due to their ability to undergo epithelial-mesenchymal transition, they modify the phenotype, bypassing the genotoxic effect of radiotherapy. It is therefore necessary to search for new methods that could improve the cytotoxic effect of cells through new mechanisms of action. Chinese medicine, with several thousand years of tradition, offers a wide range of possibilities in the search for compounds that could be used in conventional medicine. This review introduces the potential candidates that may present a radiosensitizing effect on lung cancer cells, breaking their radioresistance. Additionally, it includes candidates taken from conventional medicine-drugs commonly available in pharmacies, which may also be significant candidates.
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Affiliation(s)
- Paulina Nowak
- Scientific Club of Specialized Biological Analyzes, Faculty of Pharmacy, Wroclaw Medical University, Borowska 211A, 50-556 Wroclaw, Poland
| | - Iwona Bil-Lula
- Department of Medical Laboratory Diagnostics, Division of Clinical Chemistry and Laboratory Hematology, Faculty of Pharmacy, Wroclaw Medical University, Borowska 211A, 50-556 Wroclaw, Poland
| | - Mariola Śliwińska-Mossoń
- Department of Medical Laboratory Diagnostics, Division of Clinical Chemistry and Laboratory Hematology, Faculty of Pharmacy, Wroclaw Medical University, Borowska 211A, 50-556 Wroclaw, Poland
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Ghafouri-Fard S, Harsij A, Hussen BM, Taheri M, Sharifi G. A review on the role of CASC11 in cancers. Front Cell Dev Biol 2023; 11:1131199. [PMID: 37427385 PMCID: PMC10326515 DOI: 10.3389/fcell.2023.1131199] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2022] [Accepted: 06/16/2023] [Indexed: 07/11/2023] Open
Abstract
The long non-coding RNA (lncRNA) cancer susceptibility 11 (CASC11) is a newly identified lncRNA located on chromosome 8q24.21. The expression of lncRNA CASC11 has been found to be elevated in different cancer types and the prognosis of the tumor is inversely correlated with the high CASC11 expression. Moreover, lncRNA CASC11 has an oncogenic function in cancers. The biological characteristics of the tumors, such as proliferation, migration, invasion, autophagy, and apoptosis can be controlled by this lncRNA. In addition to interacting with miRNAs, proteins, transcription factors, and other molecules, the lncRNA CASC11 modulates signaling pathways including Wnt/β-catenin and epithelial-mesenchymal transition. In this review, we have summarized studies on the role of lncRNA CASC11 in the carcinogenesis from cell lines, in vivo, and clinical perspectives.
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Affiliation(s)
- Soudeh Ghafouri-Fard
- Department of Medical Genetics, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Atefeh Harsij
- Phytochemistry Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Bashdar Mahmud Hussen
- Department of Clinical Analysis, College of Pharmacy, Hawler Medical University, Erbil, Iraq
| | - Mohammad Taheri
- Institute of Human Genetics, Jena University Hospital, Jena, Germany
- Urology and Nephrology Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Guive Sharifi
- Skull Base Research Center, Loghman Hakim Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran
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Vijayakumar S, DiGuiseppi JA, Dabestani J, Ryan WG, Vielman Quevedo R, Li Y, Diers J, Tu S, Fleegel J, Nguyen C, Rhoda LM, Imami AS, Hamoud AAR, Lovas S, McCullumsmith R, Zallocchi M, Zuo J. In Silico Transcriptome-based Screens Identify Epidermal Growth Factor Receptor Inhibitors as Therapeutics for Noise-induced Hearing Loss. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.06.07.544128. [PMID: 37333346 PMCID: PMC10274759 DOI: 10.1101/2023.06.07.544128] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/20/2023]
Abstract
Noise-Induced Hearing Loss (NIHL) represents a widespread disease for which no therapeutics have been approved by the Food and Drug Administration (FDA). Addressing the conspicuous void of efficacious in vitro or animal models for high throughput pharmacological screening, we utilized an in silico transcriptome-oriented drug screening strategy, unveiling 22 biological pathways and 64 promising small molecule candidates for NIHL protection. Afatinib and zorifertinib, both inhibitors of the Epidermal Growth Factor Receptor (EGFR), were validated for their protective efficacy against NIHL in experimental zebrafish and murine models. This protective effect was further confirmed with EGFR conditional knockout mice and EGF knockdown zebrafish, both demonstrating protection against NIHL. Molecular analysis using Western blot and kinome signaling arrays on adult mouse cochlear lysates unveiled the intricate involvement of several signaling pathways, with particular emphasis on EGFR and its downstream pathways being modulated by noise exposure and Zorifertinib treatment. Administered orally, Zorifertinib was successfully detected in the perilymph fluid of the inner ear in mice with favorable pharmacokinetic attributes. Zorifertinib, in conjunction with AZD5438 - a potent inhibitor of cyclin dependent kinase 2 - produced synergistic protection against NIHL in the zebrafish model. Collectively, our findings underscore the potential application of in silico transcriptome-based drug screening for diseases bereft of efficient screening models and posit EGFR inhibitors as promising therapeutic agents warranting clinical exploration for combatting NIHL. Highlights In silico transcriptome-based drug screens identify pathways and drugs against NIHL.EGFR signaling is activated by noise but reduced by zorifertinib in mouse cochleae.Afatinib, zorifertinib and EGFR knockout protect against NIHL in mice and zebrafish.Orally delivered zorifertinib has inner ear PK and synergizes with a CDK2 inhibitor.
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Zhang H, Feng H, Yu T, Zhang M, Liu Z, Ma L, Liu H. Construction of an oxidative stress-related lncRNAs signature to predict prognosis and the immune response in gastric cancer. Sci Rep 2023; 13:8822. [PMID: 37258567 DOI: 10.1038/s41598-023-35167-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2023] [Accepted: 05/13/2023] [Indexed: 06/02/2023] Open
Abstract
Oxidative stress, as a characteristic of cellular aerobic metabolism, plays a crucial regulatory role in the development and metastasis of gastric cancer (GC). Long noncoding RNAs (lncRNAs) are important regulators in GC development. However, research on the prognostic patterns of oxidative stress-related lncRNAs (OSRLs) and their functions in the immune microenvironment is currently insufficient. We identified the OSRLs signature (DIP2A-IT1, DUXAP8, TP53TG1, SNHG5, AC091057.1, AL355001.1, ARRDC1-AS1, and COLCA1) from 185 oxidative stress-related genes in The Cancer Genome Atlas (TCGA) cohort via random survival forest and Cox analyses, and the results were subsequently validated in the Gene Expression Omnibus (GEO) dataset. The patients were divided into high- and low-risk groups by the risk score of the OSRLs signature. Longer overall survival was detected in the low-risk group than in the high-risk group in both the TCGA cohort (P < 0. 001, HR = 0.43, 95% CI 0.31-0.62) and the GEO cohort (P = 0.014, HR = 0.67, 95% CI 0.48-0.93). Next, multivariate Cox analysis identified that the risk model was an independent prognostic characteristic (HR > 1, P = 0.005), and time-dependent receiver operating characteristic (ROC) curve analysis and nomogram analysis were utilized to evaluate the predictive ability of the risk model. Next, gene set enrichment analysis revealed that the immune-related pathway, Wnt/[Formula: see text]-catenin signature, mammalian target of rapamycin complex 1 signature, and cytokine‒cytokine receptor interaction was enriched. High-risk patients were more responsive to CD200, TNFSF4, TNFSF9, and BTNL2 immune checkpoint blockade. The results of qRT‒PCR further proved the accuracy of our bioinformatic analysis. Overall, our study identified a novel OSRLs signature that can serve as a promising biomarker and prognostic indicator, which provides a personalized predictive approach for patient prognosis evaluation and treatment.
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Affiliation(s)
- Hui Zhang
- School of Life Science, Liaoning University, Shenyang, 110036, China
| | - Huawei Feng
- School of Pharmaceutical Sciences, Liaoning University, Shenyang, 110036, China
- Key Laboratory of Computational Simulation and Information Processing of Biomacromolecules of Liaoning Province, Shenyang, 110036, China
- Liaoning Provincial Engineering Laboratory of Molecular Modeling and Design for Drug, Shenyang, 110036, China
- Key Laboratory for Simulating Computation and Information Processing of Bio-Macromolecules of Shenyang, Shenyang, 110036, China
| | - Tiansong Yu
- School of Pharmaceutical Sciences, Liaoning University, Shenyang, 110036, China
| | - Man Zhang
- School of Life Science, Liaoning University, Shenyang, 110036, China
| | - Zhikui Liu
- Liaoning Huikang Testing and Evaluation Technology Co, Shenyang, 110036, China
| | - Lidan Ma
- Dandong Customs Integrated Technical Service Center, Dandong, 118000, China
| | - Hongsheng Liu
- School of Pharmaceutical Sciences, Liaoning University, Shenyang, 110036, China.
- Key Laboratory of Computational Simulation and Information Processing of Biomacromolecules of Liaoning Province, Shenyang, 110036, China.
- Liaoning Provincial Engineering Laboratory of Molecular Modeling and Design for Drug, Shenyang, 110036, China.
- Key Laboratory for Simulating Computation and Information Processing of Bio-Macromolecules of Shenyang, Shenyang, 110036, China.
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20
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Hosseini SA, Haddadi MH, Fathizadeh H, Nemati F, Aznaveh HM, Taraj F, Aghabozorgizadeh A, Gandomkar G, Bazazzadeh E. Long non-coding RNAs and gastric cancer: An update of potential biomarkers and therapeutic applications. Biomed Pharmacother 2023; 163:114407. [PMID: 37100014 DOI: 10.1016/j.biopha.2023.114407] [Citation(s) in RCA: 6] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2022] [Revised: 02/12/2023] [Accepted: 02/15/2023] [Indexed: 04/28/2023] Open
Abstract
The frequent metastasis of gastric cancer (GC) complicates the cure and therefore the development of effective diagnostic and therapeutic approaches is urgently necessary. In recent years, lncRNA has emerged as a drug target in the treatment of GC, particularly in the areas of cancer immunity, cancer metabolism, and cancer metastasis. This has led to the demonstration of the importance of these RNAs as prognostic, diagnostic and therapeutic agents. In this review, we provide an overview of the biological activities of lncRNAs in GC development and update the latest pathological activities, prognostic and diagnostic strategies, and therapeutic options for GC-related lncRNAs.
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Affiliation(s)
- Sayedeh Azimeh Hosseini
- Department of Medical Biotechnology, School of Advanced Technology, Shahrekord University of Medical Sciences, Shahrekord, Iran; Student Research Committee, Shahrekord University of Medical Sciences, Shahrekord, Iran; USERN office, Shahrekord University of Medical Sciences, Shahrekord, Iran
| | | | - Hadis Fathizadeh
- Student Research Committee, Sirjan School of Medical Sciences, Sirjan, Iran; Department of Laboratory sciences, Sirjan School of Medical Sciences, Sirjan, Iran
| | - Foroogh Nemati
- Department of Microbiology, Kashan University of Medical Sciences, Kashan, Iran
| | - Hooman Mahmoudi Aznaveh
- Department of Nanobiotechnology, Faculty of Biological Sciences, Tarbiat Modares University, P.O. Box: 14115-154, Tehran, Iran
| | - Farima Taraj
- Department of Animal Biotechnology, Cell Science Research Center, Royan Institute for Biotechnology, ACECR, Isfahan, Iran
| | - AmirArsalan Aghabozorgizadeh
- Department of Cell and Molecular Biology and Microbiology, Faculty of Science and Technology, University of Isfahan, Isfahan, Iran
| | - Golmaryam Gandomkar
- Department of Animal Biotechnology, Cell Science Research Center, Royan Institute for Biotechnology, ACECR, Isfahan, Iran
| | - Elaheh Bazazzadeh
- Department of Nanobiotechnology, Faculty of Biological Sciences, Tarbiat Modares University, P.O. Box: 14115-154, Tehran, Iran
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21
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Fadaei M, Kohansal M, Akbarpour O, Sami M, Ghanbariasad A. Network and functional analyses of differentially expressed genes in gastric cancer provide new biomarkers associated with disease pathogenesis. J Egypt Natl Canc Inst 2023; 35:8. [PMID: 37032412 DOI: 10.1186/s43046-023-00164-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2022] [Accepted: 02/13/2023] [Indexed: 04/11/2023] Open
Abstract
BACKGROUND Gastric cancer is a dominant source of cancer-related death around the globe and a serious threat to human health. However, there are very few practical diagnostic approaches and biomarkers for the treatment of this complex disease. METHODS This study aimed to evaluate the association between differentially expressed genes (DEGs), which may function as potential biomarkers, and the diagnosis and treatment of gastric cancer (GC). We constructed a protein-protein interaction network from DEGs followed by network clustering. Members of the two most extensive modules went under the enrichment analysis. We introduced a number of hub genes and gene families playing essential roles in oncogenic pathways and the pathogenesis of gastric cancer. Enriched terms for Biological Process were obtained from the "GO" repository. RESULTS A total of 307 DEGs were identified between GC and their corresponding normal adjacent tissue samples in GSE63089 datasets, including 261 upregulated and 261 downregulated genes. The top five hub genes in the PPI network were CDK1, CCNB1, CCNA2, CDC20, and PBK. They are involved in focal adhesion formation, extracellular matrix remodeling, cell migration, survival signals, and cell proliferation. No significant survival result was found for these hub genes. CONCLUSIONS Using comprehensive analysis and bioinformatics methods, important key pathways and pivotal genes related to GC progression were identified, potentially informing further studies and new therapeutic targets for GC treatment.
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Affiliation(s)
- Mousa Fadaei
- Noncommunicable Diseases Research Center, Fasa University of Medical Sciences, Fasa, Iran
| | - Maryam Kohansal
- Department of Medical Biotechnology, Fasa University of Medical Sciences, Fasa, Iran
- Department of Biology, Payame Noor University, Tehran, Iran
| | | | - Mahsa Sami
- Noncommunicable Diseases Research Center, Fasa University of Medical Sciences, Fasa, Iran
| | - Ali Ghanbariasad
- Noncommunicable Diseases Research Center, Fasa University of Medical Sciences, Fasa, Iran.
- Department of Medical Biotechnology, Fasa University of Medical Sciences, Fasa, Iran.
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22
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Shi X, Li M, Huang Q, Xie L, Huang Z. Monacolin K Induces Apoptosis of Human Glioma U251 Cells by Triggering ROS-Mediated Oxidative Damage and Regulating MAPKs and NF-κB Pathways. ACS Chem Neurosci 2023; 14:1331-1341. [PMID: 36917811 DOI: 10.1021/acschemneuro.3c00104] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/16/2023] Open
Abstract
Monacolin K (MK), a polyketo secondary metabolic compound of the mold genus Monascus, can promote the apoptosis of malignant cancer cells, possessing potential antitumor properties. However, its mechanism of action on gliomas remains unclear. Here, we explored and investigated the potential of the monacolin K's antitumor effect on human glioma U251 cells and its possible molecular mechanism. Results showed that the application of 10 μM monacolin K inhibited the proliferation of U251 cells, with an inhibitory rate of up to 53.4%. Additionally, monacolin K induced the generation of reactive oxygen species and activated mitochondria-mediated pathways, including decreased MMP, activation of caspase3/caspase9, decreased Na+/K+-ATPase and Ca2+-ATPase activities, and disruption of the antioxidant system, resulting in the disruption of intracellular reduction-oxidation homeostasis. Monacolin K also activated MAPK and NF-κB pathways, upregulating P38 activity and downregulating JNK/ERK/P65/IκBα expression, ultimately leading to apoptosis of U251 cells. Importantly, monacolin K was not cytotoxic to normal human cells, hUC-MSCs. We concluded that monacolin K can induce apoptosis in U251 cells by triggering ROS-mediated oxidative damage and regulating MAPKs and NF-κB pathways.
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Affiliation(s)
- Xiaoyi Shi
- State Key Laboratory of Food Science and Technology, Nanchang University, No. 235 Nanjing East Road, Nanchang 330047, China.,Sino-German Joint Research Institute, Nanchang University, No. 235 Nanjing East Road, Nanchang 330047, China
| | - Meng Li
- State Key Laboratory of Food Science and Technology, Nanchang University, No. 235 Nanjing East Road, Nanchang 330047, China.,Sino-German Joint Research Institute, Nanchang University, No. 235 Nanjing East Road, Nanchang 330047, China
| | - Qiming Huang
- College of Life Sciences, Nanchang University, No. 999 Xuefu Avenue, Nanchang 330031, China.,The National Engineering Research Center for Bioengineering Drugs and the Technologies, Institute of Translational Medicine, Nanchang University, Nanchang 330031, China
| | - Liuming Xie
- State Key Laboratory of Food Science and Technology, Nanchang University, No. 235 Nanjing East Road, Nanchang 330047, China.,Sino-German Joint Research Institute, Nanchang University, No. 235 Nanjing East Road, Nanchang 330047, China
| | - Zhibing Huang
- State Key Laboratory of Food Science and Technology, Nanchang University, No. 235 Nanjing East Road, Nanchang 330047, China.,Sino-German Joint Research Institute, Nanchang University, No. 235 Nanjing East Road, Nanchang 330047, China
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23
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Artificial intelligence-guided discovery of gastric cancer continuum. Gastric Cancer 2023; 26:286-297. [PMID: 36692601 PMCID: PMC9871434 DOI: 10.1007/s10120-022-01360-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/16/2022] [Accepted: 12/19/2022] [Indexed: 01/25/2023]
Abstract
BACKGROUND Detailed understanding of pre-, early and late neoplastic states in gastric cancer helps develop better models of risk of progression to gastric cancers (GCs) and medical treatment to intercept such progression. METHODS We built a Boolean implication network of gastric cancer and deployed machine learning algorithms to develop predictive models of known pre-neoplastic states, e.g., atrophic gastritis, intestinal metaplasia (IM) and low- to high-grade intestinal neoplasia (L/HGIN), and GC. Our approach exploits the presence of asymmetric Boolean implication relationships that are likely to be invariant across almost all gastric cancer datasets. Invariant asymmetric Boolean implication relationships can decipher fundamental time-series underlying the biological data. Pursuing this method, we developed a healthy mucosa → GC continuum model based on this approach. RESULTS Our model performed better against publicly available models for distinguishing healthy versus GC samples. Although not trained on IM and L/HGIN datasets, the model could identify the risk of progression to GC via the metaplasia → dysplasia → neoplasia cascade in patient samples. The model could rank all publicly available mouse models for their ability to best recapitulate the gene expression patterns during human GC initiation and progression. CONCLUSIONS A Boolean implication network enabled the identification of hitherto undefined continuum states during GC initiation. The developed model could now serve as a starting point for rationalizing candidate therapeutic targets to intercept GC progression.
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24
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Liu Q, Gu L, Qiu J, Qian J. Elevated NDC1 expression predicts poor prognosis and correlates with immunity in hepatocellular carcinoma. J Gastrointest Oncol 2023; 14:245-264. [PMID: 36915467 PMCID: PMC10007937 DOI: 10.21037/jgo-22-1166] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/25/2022] [Accepted: 02/02/2023] [Indexed: 03/02/2023] Open
Abstract
Background NDC1 was identified to be a tumor-promoting factor in non-small cell lung cancer and cervical cancer. However, no report had clarified the relationship between NDC1 and hepatocellular carcinoma (HCC). In this paper, we explored the expression and potential functions of NDC1 in HCC for the first time through the rational application of bioinformatics and relevant basic experiments. Methods NDC1-related expression profiles and clinical data of HCC patients were collected from The Cancer Genome Atlas (TCGA) database, which were verified via quantitative real-time polymerase chain reaction (qRT-PCR), immunohistochemistry and the Clinical Proteomic Tumor Analysis Consortium (CPTAC) database. Univariate and multivariate Cox regression analyses were used to identify NDC1 as an independent factor for HCC prognosis, and NDC1-related signaling pathways were determined by gene set enrichment analysis (GSEA). Furthermore, we deeply probed the potential links of NDC1 to immunity and immune response. Finally, the bioeffects and underlying mechanisms of ectopic NDC1 overexpression and depletion were determined in HepG2 cells by immunoblotting, flow cytometry, Cell-Counting-Kit-8 (CCK-8), and EDU (5-Ethynyl-2'-deoxyuridine). Results Up-regulated expression of NDC1 was detected by means of the TCGA database, which was consistent with the results obtained from further qRT-PCR, immunohistochemistry and the CPTAC database. Kaplan-Meier (K-M) survival analysis revealed a worse prognosis in HCC patients with high NDC1 expression. Besides, NDC1 was certified to be closely linked to tumor histologic grade, clinical stage and T stage. Moreover, univariate and multivariate Cox regression analyses defined NDC1 as an independent element for HCC prognosis. NDC1-related signaling pathways, utilizing GSEA analysis, were subsequently found out. What's more, NDC1 expression was detected to be enormously associated with microsatellite instability (MSI), immune cell infiltration, immune checkpoint molecules and immune cell pathways. As for immunotherapy, we discovered that different risk groups tended to have different immune checkpoint inhibitor responses, which indicated crucial implication value of NDC1 for HCC immunotherapy. More interestingly, we observed that the overexpression of NDC1 could promote the migration and invasion of HCC cells. Conclusions Our article demonstrated that NDC1 might serve as a valuable predictor in the prognosis and immunotherapy of HCC. NDC1 played an oncogenic role in HCC.
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Affiliation(s)
- Qingqing Liu
- Department of Gastroenterology, The Second Affiliated Hospital of Nantong University, Nantong, China.,Department of Gastroenterology, The First People's Hospital of Nantong, Nantong, China
| | - Liugen Gu
- Department of Gastroenterology, The Second Affiliated Hospital of Nantong University, Nantong, China.,Department of Gastroenterology, The First People's Hospital of Nantong, Nantong, China
| | - Jianwei Qiu
- Department of Gastroenterology, The Second Affiliated Hospital of Nantong University, Nantong, China.,Department of Gastroenterology, The First People's Hospital of Nantong, Nantong, China
| | - Junbo Qian
- Department of Gastroenterology, The Second Affiliated Hospital of Nantong University, Nantong, China.,Department of Gastroenterology, The First People's Hospital of Nantong, Nantong, China
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25
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Javed A, Yarmohammadi M, Korkmaz KS, Rubio-Tomás T. The Regulation of Cyclins and Cyclin-Dependent Kinases in the Development of Gastric Cancer. Int J Mol Sci 2023; 24:ijms24032848. [PMID: 36769170 PMCID: PMC9917736 DOI: 10.3390/ijms24032848] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/25/2022] [Revised: 01/23/2023] [Accepted: 01/28/2023] [Indexed: 02/05/2023] Open
Abstract
Gastric cancer predominantly occurs in adenocarcinoma form and is characterized by uncontrolled growth and metastases of gastric epithelial cells. The growth of gastric cells is regulated by the action of several major cell cycle regulators including Cyclins and Cyclin-dependent kinases (CDKs), which act sequentially to modulate the life cycle of a living cell. It has been reported that inadequate or over-activity of these molecules leads to disturbances in cell cycle dynamics, which consequently results in gastric cancer development. Manny studies have reported the key roles of Cyclins and CDKs in the development and progression of the disease in either in vitro cell culture studies or in vivo models. We aimed to compile the evidence of molecules acting as regulators of both Cyclins and CDKs, i.e., upstream regulators either activating or inhibiting Cyclins and CDKs. The review entails an introduction to gastric cancer, along with an overview of the involvement of cell cycle regulation and focused on the regulation of various Cyclins and CDKs in gastric cancer. It can act as an extensive resource for developing new hypotheses for future studies.
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Affiliation(s)
- Aadil Javed
- Department of Bioengineering, Faculty of Engineering, Cancer Biology Laboratory, Ege University, Izmir 35040, Turkey
- Correspondence: (A.J.); (T.R.-T.)
| | - Mahdieh Yarmohammadi
- Department of Biology, Faculty of Sciences, Central Tehran Branch, Islamic Azad University, Tehran 33817-74895, Iran
| | - Kemal Sami Korkmaz
- Department of Bioengineering, Faculty of Engineering, Cancer Biology Laboratory, Ege University, Izmir 35040, Turkey
| | - Teresa Rubio-Tomás
- School of Medicine, University of Crete, 70013 Herakleion, Crete, Greece
- Correspondence: (A.J.); (T.R.-T.)
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26
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Qu X, Liu B, Wang L, Liu L, Zhao W, Liu C, Ding J, Zhao S, Xu B, Yu H, Zhang X, Chai J. Loss of cancer-associated fibroblast-derived exosomal DACT3-AS1 promotes malignant transformation and ferroptosis-mediated oxaliplatin resistance in gastric cancer. Drug Resist Updat 2023; 68:100936. [PMID: 36764075 DOI: 10.1016/j.drup.2023.100936] [Citation(s) in RCA: 33] [Impact Index Per Article: 33.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2022] [Revised: 01/09/2023] [Accepted: 01/20/2023] [Indexed: 02/01/2023]
Abstract
AIMS Long non-coding RNAs (lncRNAs), as one of the components of exosomes derived from cancer-associated fibroblasts (CAFs), exhibit a crucial role in the pathogenesis and chemoresistance of gastric cancer (GC). Herein, we investigated the role and mechanism of a novel lncRNA disheveled binding antagonist of beta catenin3 antisense1 (DACT3-AS1) and its involvement in GC. METHODS DACT3-AS1 was identified by RNA-sequencing and verified by quantitative reverse transcription polymerase chain reaction (qRT-PCR). The functional role of DACT3-AS1 in GC was evaluated using in vitro and in vivo experiments including Transwell assay, 5-Ethynyl-2'-deoxyuridine (EdU) assay, immunoblotting, and xenograft tumor mouse model. Dual-luciferase reporter assay was performed to assess the association between genes. RESULTS DACT3-AS1 was downregulated and involved in poor prognosis of patients with GC. The results from both in vitro and in vivo experiments showed that DACT3-AS1 suppressed cell proliferation, migration, and invasion through targeting miR-181a-5p/sirtuin 1 (SIRT1) axis. Additionally, DACT3-AS1 was transmitted from CAFs to GC cells mainly via exosomes. Exosomal DACT3-AS1 alleviated xenograft tumor growth. DACT3-AS1 conferred sensitivity of cancer cells to oxaliplatin through SIRT1-mediated ferroptosis both in vitro and in vivo. CONCLUSIONS CAFs-derived exosomal DACT3-AS1 is a suppressive regulator in malignant transformation and oxaliplatin resistance. DACT3-AS1 could be used for diagnosis and treatment of GC.
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Affiliation(s)
- Xianlin Qu
- Department of Gastrointestinal Surgery, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Science, Jinan, Shandong, China
| | - Bing Liu
- Department of Gastrointestinal Surgery, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Science, Jinan, Shandong, China
| | - Longgang Wang
- Department of Gastrointestinal Surgery, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Science, Jinan, Shandong, China
| | - Luguang Liu
- Department of Gastrointestinal Surgery, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Science, Jinan, Shandong, China
| | - Weizhu Zhao
- Department of Radiology, Shandong University, Shandong Cancer Hospital and Institute, Jinan, Shandong, China; Department of Oncology, Binzhou People's Hospital Affiliated to Shandong First Medical University, Binzhou, Shandong, China
| | - Changlei Liu
- Department of scientific research project, Shandong Excalibur Medical Research. LTD, Jinan, Shandong, China
| | - Jishuang Ding
- Department of Gastrointestinal Surgery, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Science, Jinan, Shandong, China
| | - Siwei Zhao
- Department of Gastrointestinal Surgery, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Science, Jinan, Shandong, China
| | - Botao Xu
- Department of Gastrointestinal Surgery, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Science, Jinan, Shandong, China
| | - Hang Yu
- Department of Gastrointestinal Surgery, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Science, Jinan, Shandong, China
| | - Xiang Zhang
- Department of scientific research project, Shandong Excalibur Medical Research. LTD, Jinan, Shandong, China
| | - Jie Chai
- Department of Gastrointestinal Surgery, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Science, Jinan, Shandong, China.
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27
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Data mining combines bioinformatics discover immunoinfiltration-related gene SERPINE1 as a biomarker for diagnosis and prognosis of stomach adenocarcinoma. Sci Rep 2023; 13:1373. [PMID: 36697459 PMCID: PMC9876925 DOI: 10.1038/s41598-023-28234-7] [Citation(s) in RCA: 8] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2022] [Accepted: 01/16/2023] [Indexed: 01/27/2023] Open
Abstract
Stomach adenocarcinoma (STAD) is a type of cancer which often at itsadvanced stage apon diagnosis and mortality in clinical practice. Several factors influencethe prognosis of STAD, including the expression and regulation of immune cells in the tumor microenvironment. We here investigated the biomarkers related to the diagnosis and prognosis of gastric cancer, hoping to provide insights for the diagnosis and treatment of gastric cancer in the future. STAD and normal patient RNA sequencing data sets were accessed from the cancer genome atlas (TCGA database). Differential genes were determined and obtained by using the R package DESeq2. The stromal, immune, and ESTIMATE scores are calculated by the ESTIMATE algorithm, followed by the modular genes screening using the R package WGCNA. Subsequently, the intersection between the modular gene and the differential gene was taken and the STRING database was used for PPI network module analysis. The R packages clusterProfiler, enrichplot, and ggplot2 were used for GO and KEGG enrichment analysis. Cox regression analysis was used to screen survival-related genes, and finally, the R package Venn Diagram was used to take the intersection and obtain 7 hub genes. The time-dependent ROC curve and Kaplan-Meier survival curve were used to find the SERPINE1 gene, which plays a critical role in prognosis. Finally, the expression pattern, clinical characteristics, and regulatory mechanism of SERPINE1 were analyzed in STAD. We revealed that the expression of SERPINE1 was significantly increased in the samples from STAD compared with normal samples. Cox regression, time-dependent ROC, and Kaplan-Meier survival analyses demonstrated that SERPINE1 was significantly related to the adverse prognosis of STAD patients. The expression of SERPINE1 increased with the progression of T, N, and M classification of the tumor. In addition, the results of immune infiltration analysis indicated that the immune cells' expression were higher in high SERPINE1 expression group than that in low SERPINE1 expression group, including CD4+ T cells, B cells, CD8+ T cells, macrophages, neutrophils and other immune cells. SERPINE1 was closely related to immune cells in the STAD immune microenvironment and had a synergistic effect with the immune checkpoints PD1 and PD-L1. In conclusion, we proved that SERPINE1 is a promising prognostic and diagnostic biomarker for STAD and a potential target for immunotherapy.
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28
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Petrosyan V, Dobrolecki LE, Thistlethwaite L, Lewis AN, Sallas C, Srinivasan RR, Lei JT, Kovacevic V, Obradovic P, Ellis MJ, Osborne CK, Rimawi MF, Pavlick A, Shafaee MN, Dowst H, Jain A, Saltzman AB, Malovannaya A, Marangoni E, Welm AL, Welm BE, Li S, Wulf GM, Sonzogni O, Huang C, Vasaikar S, Hilsenbeck SG, Zhang B, Milosavljevic A, Lewis MT. Identifying biomarkers of differential chemotherapy response in TNBC patient-derived xenografts with a CTD/WGCNA approach. iScience 2023; 26:105799. [PMID: 36619972 PMCID: PMC9813793 DOI: 10.1016/j.isci.2022.105799] [Citation(s) in RCA: 13] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2022] [Revised: 07/20/2022] [Accepted: 12/08/2022] [Indexed: 12/14/2022] Open
Abstract
Although systemic chemotherapy remains the standard of care for TNBC, even combination chemotherapy is often ineffective. The identification of biomarkers for differential chemotherapy response would allow for the selection of responsive patients, thus maximizing efficacy and minimizing toxicities. Here, we leverage TNBC PDXs to identify biomarkers of response. To demonstrate their ability to function as a preclinical cohort, PDXs were characterized using DNA sequencing, transcriptomics, and proteomics to show consistency with clinical samples. We then developed a network-based approach (CTD/WGCNA) to identify biomarkers of response to carboplatin (MSI1, TMSB15A, ARHGDIB, GGT1, SV2A, SEC14L2, SERPINI1, ADAMTS20, DGKQ) and docetaxel (c, MAGED4, CERS1, ST8SIA2, KIF24, PARPBP). CTD/WGCNA multigene biomarkers are predictive in PDX datasets (RNAseq and Affymetrix) for both taxane- (docetaxel or paclitaxel) and platinum-based (carboplatin or cisplatin) response, thereby demonstrating cross-expression platform and cross-drug class robustness. These biomarkers were also predictive in clinical datasets, thus demonstrating translational potential.
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Affiliation(s)
- Varduhi Petrosyan
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA
| | - Lacey E. Dobrolecki
- Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, TX 77030, USA
| | - Lillian Thistlethwaite
- Quantitative and Computational Biosciences Program, Baylor College of Medicine, Houston, TX 77030, USA
| | - Alaina N. Lewis
- Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, TX 77030, USA
| | - Christina Sallas
- Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, TX 77030, USA
| | | | - Jonathan T. Lei
- Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, TX 77030, USA
| | - Vladimir Kovacevic
- School of Electrical Engineering, University of Belgrade, Belgrade, Serbia
| | - Predrag Obradovic
- School of Electrical Engineering, University of Belgrade, Belgrade, Serbia
| | - Matthew J. Ellis
- Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, TX 77030, USA
- Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA
| | - C. Kent Osborne
- Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, TX 77030, USA
- Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA
| | - Mothaffar F. Rimawi
- Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, TX 77030, USA
- Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA
| | - Anne Pavlick
- Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, TX 77030, USA
| | - Maryam Nemati Shafaee
- Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, TX 77030, USA
| | - Heidi Dowst
- Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA
| | - Antrix Jain
- Mass Spectrometry Proteomics Core, Baylor College of Medicine, Houston, TX 77030, USA
| | - Alexander B. Saltzman
- Mass Spectrometry Proteomics Core, Baylor College of Medicine, Houston, TX 77030, USA
| | - Anna Malovannaya
- Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA
- Verna and Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, TX 77030, USA
- Mass Spectrometry Proteomics Core, Baylor College of Medicine, Houston, TX 77030, USA
- Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA
| | | | - Alana L. Welm
- Department of Oncological Sciences, University of Utah, Salt Lake City, UT 84112, USA
- Huntsman Cancer Institute, University of Utah, Salt Lake City, UT 84112, USA
| | - Bryan E. Welm
- Department of Surgery, University of Utah, Salt Lake City, UT 84112, USA
- Huntsman Cancer Institute, University of Utah, Salt Lake City, UT 84112, USA
| | - Shunqiang Li
- Division of Oncology, Washington University, St. Louis, MO 63130, USA
| | | | - Olmo Sonzogni
- Beth Israel Deaconess Medical Center, Boston, MA 02215, USA
| | - Chen Huang
- Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, TX 77030, USA
| | - Suhas Vasaikar
- Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, TX 77030, USA
| | - Susan G. Hilsenbeck
- Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, TX 77030, USA
- Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA
| | - Bing Zhang
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA
- Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, TX 77030, USA
- Quantitative and Computational Biosciences Program, Baylor College of Medicine, Houston, TX 77030, USA
| | - Aleksandar Milosavljevic
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA
- Quantitative and Computational Biosciences Program, Baylor College of Medicine, Houston, TX 77030, USA
| | - Michael T. Lewis
- Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, TX 77030, USA
- Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA
- Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA
- Department of Radiology, Baylor College of Medicine, Houston, TX, USA
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Yang M, Wang P, Liu T, Zou X, Xia Y, Li C, Wang X. High throughput sequencing revealed enhanced cell cycle signaling in SLE patients. Sci Rep 2023; 13:159. [PMID: 36599883 DOI: 10.1038/s41598-022-27310-8] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2022] [Accepted: 12/29/2022] [Indexed: 01/05/2023] Open
Abstract
The multi-system involvement and high heterogeneity of systemic lupus erythematosus (SLE) pose great challenges to its diagnosis and treatment. The purpose of the current study is to identify genes and pathways involved in the pathogenesis of SLE. High throughput sequencing was performed on the PBMCs from SLE patients. We conducted differential gene analysis, gene ontology (GO) analysis, kyoto encyclopedia of genes and genomes (KEGG) analysis, and quantitative real-time PCR (qRT-PCR) verification. Protein-protein interaction (PPI) analysis, alternative splicing analysis, and disease correlation analysis were conducted on some key pathogenic genes as well. Furthermore, si-CDC6 was used for transfection and cell proliferation was monitored using a cell counting kit-8 (CCK-8) assay. We identified 2495 differential genes (1494 upregulated and 1001 downregulated) in SLE patients compared with healthy controls. The significantly upregulated genes were enriched in the biological process-related GO terms of the cell cycle, response to stress, and chromosome organization. KEGG enrichment analysis revealed 7 significantly upregulated pathways including SLE, alcoholism, viral carcinogenesis, cell cycle, proteasome, malaria, and transcriptional misregulation in cancer. We successfully verified some differential genes on the SLE pathway and the cell cycle pathway. CDC6, a key gene in the cell cycle pathway, had remarkably higher MXE alternative splicing events in SLE patients than that in controls, which may explain its significant upregulation in SLE patients. We found that CDC6 participates in the pathogenesis of many proliferation-related diseases and its levels are positively correlated with the severity of SLE. Knockdown of CDC6 suppressed the proliferation of Hela cells and PBMCs from SLE patients in vitro. We identified SLE-related genes and their alternative splicing events. The cell cycle pathway and the cell cycle-related biological processes are over-activated in SLE patients. We revealed a higher incidence of MXE events of CDC6, which may lead to its high expression in SLE patients. Upregulated cell cycle signaling and CDC6 may be related to the hyperproliferation and pathogenesis of SLE.
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Affiliation(s)
- Mingyue Yang
- Laboratory for Tumor Immunology, Translational Medicine Department, First Hospital of Jilin University, Changchun, 130021, China
| | - Peisong Wang
- Thyroid Surgery Department, General Surgery Center, First Hospital of Jilin University, Changchun, 130021, China
| | - Tao Liu
- Department of Rheumatology and Immunology, First Hospital of Jilin University, Changchun, 130021, China
| | - Xiaojuan Zou
- Department of Rheumatology and Immunology, First Hospital of Jilin University, Changchun, 130021, China
| | - Ying Xia
- Laboratory for Tumor Immunology, Translational Medicine Department, First Hospital of Jilin University, Changchun, 130021, China
| | - Chenxu Li
- Laboratory for Tumor Immunology, Translational Medicine Department, First Hospital of Jilin University, Changchun, 130021, China
| | - Xiaosong Wang
- Laboratory for Tumor Immunology, Translational Medicine Department, First Hospital of Jilin University, Changchun, 130021, China.
- Institute of Translational Medicine, First Hospital of Jilin University, No.519 Dongminzhu Street, Changchun, 130021, China.
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Araújo D, Ribeiro E, Amorim I, Vale N. Repurposed Drugs in Gastric Cancer. MOLECULES (BASEL, SWITZERLAND) 2022; 28:molecules28010319. [PMID: 36615513 PMCID: PMC9822219 DOI: 10.3390/molecules28010319] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 10/01/2022] [Revised: 12/21/2022] [Accepted: 12/25/2022] [Indexed: 01/04/2023]
Abstract
Gastric cancer (GC) is one of the major causes of death worldwide, ranking as the fifth most incident cancer in 2020 and the fourth leading cause of cancer mortality. The majority of GC patients are in an advanced stage at the time of diagnosis, presenting a poor prognosis and outcome. Current GC treatment approaches involve endoscopic detection, gastrectomy and chemotherapy or chemoradiotherapy in an adjuvant or neoadjuvant setting. Drug development approaches demand extreme effort to identify molecular mechanisms of action of new drug candidates. Drug repurposing is based on the research of new therapeutic indications of drugs approved for other pathologies. In this review, we explore GC and the different drugs repurposed for this disease.
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Affiliation(s)
- Diana Araújo
- OncoPharma Research Group, Center for Health Technology and Services Research (CINTESIS), Rua Doutor Plácido da Costa, 4200-450 Porto, Portugal
- Institute of Biomedical Sciences Abel Salazar (ICBAS), Universidade do Porto (UP), Rua de Jorge Viterbo Ferreira 228, 4050-313 Porto, Portugal
- Institute for Research and Innovation in Health (i3S), Universidade do Porto, Rua Alfredo Allen, 208, 4200-135 Porto, Portugal
- Institute of Molecular Pathology and Immunology, University of Porto (IPATIMUP), Rua Júlio Amaral de Carvalho, 45, 4200-135 Porto, Portugal
| | - Eduarda Ribeiro
- OncoPharma Research Group, Center for Health Technology and Services Research (CINTESIS), Rua Doutor Plácido da Costa, 4200-450 Porto, Portugal
- Institute of Biomedical Sciences Abel Salazar (ICBAS), Universidade do Porto (UP), Rua de Jorge Viterbo Ferreira 228, 4050-313 Porto, Portugal
| | - Irina Amorim
- Institute of Biomedical Sciences Abel Salazar (ICBAS), Universidade do Porto (UP), Rua de Jorge Viterbo Ferreira 228, 4050-313 Porto, Portugal
- Institute for Research and Innovation in Health (i3S), Universidade do Porto, Rua Alfredo Allen, 208, 4200-135 Porto, Portugal
- Institute of Molecular Pathology and Immunology, University of Porto (IPATIMUP), Rua Júlio Amaral de Carvalho, 45, 4200-135 Porto, Portugal
| | - Nuno Vale
- OncoPharma Research Group, Center for Health Technology and Services Research (CINTESIS), Rua Doutor Plácido da Costa, 4200-450 Porto, Portugal
- CINTESIS@RISE, Faculty of Medicine, University of Porto, Alameda Professor Hernâni Monteiro, 4200-319 Porto, Portugal
- Department of Community Medicine, Health Information and Decision (MEDCIDS), Faculty of Medicine, University of Porto, Rua Doutor Plácido da Costa, 4200-450 Porto, Portugal
- Correspondence: ; Tel.: +351-220426537
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Huang J, Chen M, Pei W, Xu Z, Ning J, Chen C. Distinct tumor microenvironment landscapes in gastric cancer classified by cuproptosis-related lncRNAs. J Cancer 2022; 13:3687-3700. [PMID: 36606199 PMCID: PMC9809317 DOI: 10.7150/jca.79640] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2022] [Accepted: 11/20/2022] [Indexed: 12/12/2022] Open
Abstract
Cuproptosis is a newly discovered non-apoptotic form of cell death that may be related to the development of tumors. Nonetheless, the potential role of cuproptosis-related lncRNAs in tumor microenvironment (TME) formation and patient-tailored treatment optimization of gastric cancer (GC) is still unclear. In this study, the six-lncRNA signature was constructed to quantify the molecular patterns of GC using LASSO-Cox regression model. Receiver operating characteristic (ROC) curves, C-index curves, independent prognostic analysis and principal component analysis (PCA) were conducted to verify and evaluate the model. The results showed that this risk model was accurate and reliable in predicting GC patient survival. In addition, two distinct subgroups were identified based on the risk model, which showed significant difference in biological functions of the associated genes, TME scores, characteristics of infiltrating immune cells and immunotherapy responses. We found that the high-risk subgroup was associated with immune activation and tumor-related pathways. Furthermore, compared with the low-risk subgroup, the high-risk subgroup had higher TME scores, richer immune cell infiltration and a better immunotherapy response. To accurately identify immune cold tumors and hot tumors, all samples of GC were divided into four distinct clusters by consensus clustering. Among them, Cluster 3 was identified as an immune hot tumor and was more sensitive to immunotherapy. Overall, this study demonstrates that cuproptosis-related lncRNAs could accurately predict the prognosis of patients with GC, help make a distinction between immune cold tumors and hot tumors and provide a basis for the precision medicine of GC.
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Affiliation(s)
- Jianfeng Huang
- Department of General Surgery, The First Affiliated Hospital of Anhui Medical University, 218 JiXi Avenue, Hefei 230022, Anhui, China
| | - Meixiang Chen
- The First School of Clinical Medicine, Southern Medical University, Guangzhou 510515, Guangdong, China
| | - Wenguang Pei
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Nanchang University, Nanchang 330006, Jiangxi Province, China
| | - Zhijue Xu
- Department of Vascular Surgery, Shanghai Ninth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China.,✉ Corresponding authors: Zhijue Xu, Department of Vascular Surgery, Shanghai Ninth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China. E-mail: ; Jie Ning, Department of Oncology, The First Affiliated Hospital of Anhui Medical University, 218 JiXi Avenue, Hefei 230022, Anhui, China. E-mail: ; Changyu Chen, Department of General Surgery, The First Affiliated Hospital of Anhui Medical University, 218 JiXi Avenue, Hefei 230022, Anhui, China. E-mail:
| | - Jie Ning
- Department of Oncology, The First Affiliated Hospital of Anhui Medical University, 218 JiXi Avenue, Hefei 230022, Anhui, China.,✉ Corresponding authors: Zhijue Xu, Department of Vascular Surgery, Shanghai Ninth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China. E-mail: ; Jie Ning, Department of Oncology, The First Affiliated Hospital of Anhui Medical University, 218 JiXi Avenue, Hefei 230022, Anhui, China. E-mail: ; Changyu Chen, Department of General Surgery, The First Affiliated Hospital of Anhui Medical University, 218 JiXi Avenue, Hefei 230022, Anhui, China. E-mail:
| | - Changyu Chen
- Department of General Surgery, The First Affiliated Hospital of Anhui Medical University, 218 JiXi Avenue, Hefei 230022, Anhui, China.,✉ Corresponding authors: Zhijue Xu, Department of Vascular Surgery, Shanghai Ninth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China. E-mail: ; Jie Ning, Department of Oncology, The First Affiliated Hospital of Anhui Medical University, 218 JiXi Avenue, Hefei 230022, Anhui, China. E-mail: ; Changyu Chen, Department of General Surgery, The First Affiliated Hospital of Anhui Medical University, 218 JiXi Avenue, Hefei 230022, Anhui, China. E-mail:
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Badie A, Gaiddon C, Mellitzer G. Histone Deacetylase Functions in Gastric Cancer: Therapeutic Target? Cancers (Basel) 2022; 14:5472. [PMID: 36358890 PMCID: PMC9659209 DOI: 10.3390/cancers14215472] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2022] [Revised: 10/29/2022] [Accepted: 11/01/2022] [Indexed: 09/05/2023] Open
Abstract
Gastric cancer (GC) is one of the most aggressive cancers. Therapeutic treatments are based on surgery combined with chemotherapy using a combination of platinum-based agents. However, at metastatic stages of the disease, survival is extremely low due to late diagnosis and resistance mechanisms to chemotherapies. The development of new classifications has not yet identified new prognostic markers for clinical use. The studies of epigenetic processes highlighted the implication of histone acetylation status, regulated by histone acetyltransferases (HATs) and by histone deacetylases (HDACs), in cancer development. In this way, inhibitors of HDACs (HDACis) have been developed and some of them have already been clinically approved to treat T-cell lymphoma and multiple myeloma. In this review, we summarize the regulations and functions of eighteen HDACs in GC, describing their known targets, involved cellular processes, associated clinicopathological features, and impact on survival of patients. Additionally, we resume the in vitro, pre-clinical, and clinical trials of four HDACis approved by Food and Drug Administration (FDA) in cancers in the context of GC.
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Affiliation(s)
| | | | - Georg Mellitzer
- Laboratoire Streinth, Université de Strasbourg, Inserm UMR_S 1113 IRFAC, 67200 Strasbourg, France
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Non-coding genome in small cell lung cancer between theoretical view and clinical applications. Semin Cancer Biol 2022; 86:237-250. [PMID: 35367369 DOI: 10.1016/j.semcancer.2022.03.024] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2021] [Revised: 03/22/2022] [Accepted: 03/26/2022] [Indexed: 01/27/2023]
Abstract
Small cell lung cancer (SCLC) is a highly aggressive cancer of the neuroendocrine system, characterized by poor differentiation, rapid growth, and poor overall survival (OS) of patients. Despite the recent advances in the treatment of SCLC recently, the 2-year survival rate of patients with the cancer is only 14-15%, occasioned by the acquired resistance to drugs and serious off-target effects. In humans, the coding region is only 2% of the total genome, and 20% of that is associated with human diseases. Beyond the coding genome are RNAs, promoters, enhancers, and other intricate elements. The non-coding regulatory regions, mainly the non-coding RNAs (ncRNAs), regulate numerous biological activities including cell proliferation, metastasis, and drug resistance. As such, they are potential diagnostic or prognostic biomarkers, and also potential therapeutic targets for SCLC. Therefore, understanding how non-coding elements regulate SCLC development and progression holds significant clinical implications. Herein, we summarized the recent discoveries on the relationship between the non-coding elements including long non-coding RNAs (lncRNA), microRNAs (miRNAs), circular RNA (circRNA), enhancers as well as promotors, and the pathogenesis of SCLC and their potential clinical applications.
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Bai Y, Qu D, Lu D, Li Y, Zhao N, Cui G, Li X, Sun X, Sun H, Zhao L, Li Q, Zhang Q, Han T, Wang S, Yang Y. Pan-cancer landscape of abnormal ctDNA methylation across human tumors. Cancer Genet 2022; 268-269:37-45. [PMID: 36152512 DOI: 10.1016/j.cancergen.2022.09.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2021] [Revised: 08/25/2022] [Accepted: 09/12/2022] [Indexed: 01/25/2023]
Abstract
BACKGROUND The aim of this paper is to explore the correlation between circulating tumor DNA (ctDNA) methylation and mutations and its value in clinical early cancer screening. METHODS We performed target region methylation sequencing and genome sequencing on plasma samples. Methylation models to distinguish cancer from healthy individuals have been developed using hypermethylated genes in tumors and validated in training set and prediction set. RESULTS We found that patients with cancer had higher levels of ctDNA methylation compared to healthy individuals. The level of ctDNA methylation in cell cycle, p53, Notch pathway in pan-cancer was significantly correlated with the number of mutations, and mutation frequency. Methylation burden in some tumors was significantly correlated with tumor mutational burden (TMB), microsatellite instability (MSI) and PD-L1. The ctDNA methylation differences in cancer patients were mainly concentrated in the Herpes simplex virus 1 infection pathway. The area under curve (AUC) of the training and prediction sets of the methylation model distinguishing cancer from healthy individuals were 0.93 and 0.92, respectively. CONCLUSION Our study provides a landscape of methylation levels of important pathways in pan-cancer. ctDNA methylation significantly correlates with mutation type, frequency and number, providing a reference for clinical application of ctDNA methylation in early cancer screening.
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Affiliation(s)
- Yun Bai
- Department of Medical Oncology, The Second Affiliated Hospital of Harbin Medical University, Harbin 150081, China
| | - Di Qu
- Department of Medical Oncology, The Second Affiliated Hospital of Harbin Medical University, Harbin 150081, China
| | - Dan Lu
- Department of Medical Oncology, The Second Affiliated Hospital of Harbin Medical University, Harbin 150081, China
| | - Yiwen Li
- Department of Medical Oncology, The Second Affiliated Hospital of Harbin Medical University, Harbin 150081, China
| | - Ning Zhao
- Department of Medical Oncology, The Second Affiliated Hospital of Harbin Medical University, Harbin 150081, China
| | - Guanghua Cui
- Department of Medical Oncology, The Second Affiliated Hospital of Harbin Medical University, Harbin 150081, China
| | - Xue Li
- Department of Medical Oncology, The Second Affiliated Hospital of Harbin Medical University, Harbin 150081, China
| | - Xiaoke Sun
- Department of Medical Oncology, The Second Affiliated Hospital of Harbin Medical University, Harbin 150081, China
| | - Huaibo Sun
- Genecast Biotechnology Co., Ltd, Wuxi 214104, China
| | - Lihua Zhao
- Genecast Biotechnology Co., Ltd, Wuxi 214104, China
| | - Qingyuan Li
- Genecast Biotechnology Co., Ltd, Wuxi 214104, China
| | - Qi Zhang
- Genecast Biotechnology Co., Ltd, Wuxi 214104, China
| | | | - Song Wang
- Department of Medical Oncology, Mudanjiang Cancer Hospital, Mudanjiang 157009, China.
| | - Yu Yang
- Department of Medical Oncology, The Second Affiliated Hospital of Harbin Medical University, Harbin 150081, China.
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Ghafouri-Fard S, Khoshbakht T, Hussen BM, Dong P, Gassler N, Taheri M, Baniahmad A, Dilmaghani NA. A review on the role of cyclin dependent kinases in cancers. Cancer Cell Int 2022; 22:325. [PMID: 36266723 PMCID: PMC9583502 DOI: 10.1186/s12935-022-02747-z] [Citation(s) in RCA: 17] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2022] [Accepted: 10/07/2022] [Indexed: 11/16/2022] Open
Abstract
The Cyclin-dependent kinase (CDK) class of serine/threonine kinases has crucial roles in the regulation of cell cycle transition and is mainly involved in the pathogenesis of cancers. The expression of CDKs is controlled by a complex regulatory network comprised of genetic and epigenetic mechanisms, which are dysregulated during the progression of cancer. The abnormal activation of CDKs results in uncontrolled cancer cell proliferation and the induction of cancer stem cell characteristics. The levels of CDKs can be utilized to predict the prognosis and treatment response of cancer patients, and further understanding of the function and underlying mechanisms of CDKs in human tumors would pave the way for future cancer therapies that effectively target CDKs. Defects in the regulation of cell cycle and mutations in the genes coding cell-cycle regulatory proteins lead to unrestrained proliferation of cells leading to formation of tumors. A number of treatment modalities have been designed to combat dysregulation of cell cycle through affecting expression or activity of CDKs. However, effective application of these methods in the clinical settings requires recognition of the role of CDKs in the progression of each type of cancer, their partners, their interactions with signaling pathways and the effects of suppression of these kinases on malignant features. Thus, we designed this literature search to summarize these findings at cellular level, as well as in vivo and clinical levels.
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Affiliation(s)
- Soudeh Ghafouri-Fard
- Department of Medical Genetics, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Tayyebeh Khoshbakht
- Men's Health and Reproductive Health Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Bashdar Mahmud Hussen
- Department of Pharmacognosy, College of Pharmacy, Hawler Medical University, Erbil, Kurdistan Region, Iraq.,Center of Research and Strategic Studies, Lebanese French University, Erbil, Kurdistan Region, Iraq
| | - Peixin Dong
- Department of Obstetrics and Gynecology, Hokkaido University School of Medicine, Hokkaido University, Sapporo, Japan
| | - Nikolaus Gassler
- Section of Pathology, Institute of Forensic Medicine, Jena University Hospital, Jena, Germany
| | - Mohammad Taheri
- Urology and Nephrology Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran. .,Institute of Human Genetics, Jena University Hospital, Jena, Germany.
| | - Aria Baniahmad
- Institute of Human Genetics, Jena University Hospital, Jena, Germany.
| | - Nader Akbari Dilmaghani
- Skull Base Research Center, Loghman Hakim Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
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Zafar J, Huang J, Xu X, Jin F. Analysis of Long Non-Coding RNA-Mediated Regulatory Networks of Plutella xylostella in Response to Metarhizium anisopliae Infection. INSECTS 2022; 13:916. [PMID: 36292864 PMCID: PMC9604237 DOI: 10.3390/insects13100916] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 09/15/2022] [Revised: 09/30/2022] [Accepted: 09/30/2022] [Indexed: 06/16/2023]
Abstract
Long non-coding RNAs (lncRNAs) represent a diverse class of RNAs that are structurally similar to messenger RNAs (mRNAs) but do not encode proteins. Growing evidence suggests that in response to biotic and abiotic stresses, the lncRNAs play crucial regulatory roles in plants and animals. However, the potential role of lncRNAs during fungal infection has yet to be characterized in Plutella xylostella, a devastating pest of cruciferous crops. In the current study, we performed a strand-specific RNA sequencing of Metarhizium anisopliae-infected (Px36hT, Px72hT) and uninfected (Px36hCK, Px72hCK) P. xylostella fat body tissues. Comprehensive bioinformatic analysis revealed a total of 5665 and 4941 lncRNAs at 36 and 72-h post-infection (hpi), including 563 (Px36hT), 532 (Px72hT) known and 5102 (Px36hT), 4409 (Px72hT) novel lncRNA transcripts. These lncRNAs shared structural similarities with their counterparts in other species, including shorter exon and intron length, fewer exon numbers, and a lower expression profile than mRNAs. LncRNAs regulate the expression of neighboring protein-coding genes by acting in a cis and trans manner. Functional annotation and pathway analysis of cis-acting lncRNAs revealed their role in several immune-related genes, including Toll, serpin, transferrin, βGRP etc. Furthermore, we identified multiple lncRNAs acting as microRNA (miRNA) precursors. These miRNAs can potentially regulate the expression of mRNAs involved in immunity and development, suggesting a crucial lncRNA-miRNA-mRNA complex. Our findings will provide a genetic resource for future functional studies of lncRNAs involved in P. xylostella immune responses to M. anisopliae infection and shed light on understanding insect host-pathogen interactions.
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Affiliation(s)
| | | | - Xiaoxia Xu
- Correspondence: (X.X.); (F.J.); Tel.: +86-135-6047-8369 (F.J.)
| | - Fengliang Jin
- Correspondence: (X.X.); (F.J.); Tel.: +86-135-6047-8369 (F.J.)
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Liang L, Cen H, Huang J, Qin A, Xu W, Wang S, Chen Z, Tan L, Zhang Q, Yu X, Yang X, Zhang L. The reversion of DNA methylation-induced miRNA silence via biomimetic nanoparticles-mediated gene delivery for efficient lung adenocarcinoma therapy. Mol Cancer 2022; 21:186. [PMID: 36171576 PMCID: PMC9516831 DOI: 10.1186/s12943-022-01651-4] [Citation(s) in RCA: 16] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2022] [Accepted: 08/25/2022] [Indexed: 11/21/2022] Open
Abstract
Background Lung cancer is one of the fatal cancers worldwide, and over 60% of patients are lung adenocarcinoma (LUAD). Our clinical data demonstrated that DNA methylation of the promoter region of miR-126-3p was upregulated, which led to the decreased expression of miR-126-3p in 67 cases of lung cancer tissues, implying that miR-126-3p acted as a tumor suppressor. Transduction of miR-126-3p is a potential therapeutic strategy for treating LUAD, yet the physiological environment and properties of miRNA challenge current transduction approaches. Methods We evaluated the expression of miR-126-3p in 67 pairs of lung cancer tissues and the corresponding adjacent non-tumorous tissues by Reverse transcription-quantitative polymerase chain reaction (RT-qPCR). The relationship between the overall survival of lung cancer patients and miR-126-3p was analyzed by the Cancer Genome Atlas cohort database (Oncolnc, http://www.oncolnc.org). We analyzed DNA methylation Methylation-specific PCR (MSP) analysis. To determine whether ADAM9 is the direct target of miR-126-3p, we performed the 3′-UTR luciferase reporter assay. The protein levels in the cells or tissues were evaluated with western blotting (WB) analysis. The biodistribution of nanoparticles were monitored by in vivo tracking system. Results We describe the development of novel stealth and matrix metalloproteinase 2 (MMP2)-activated biomimetic nanoparticles, which are constructed using MMP2-responsive peptides to bind the miR-126-3p (known as MAIN), and further camouflaged with red blood cell (RBC) membranes (hence named REMAIN). REMAIN was able to effectively transduce miRNA into lung cancer cells and release them via MMP2 responsiveness. Additionally, REMAIN possessed the advantages of the natural RBC membrane, including extended circulation time, lower toxicity, better biocompatibility, and immune escape. Moreover, in vitro and in vivo results demonstrated that REMAIN effectively induced apoptosis of lung cancer cells and inhibited LUAD development and progression by targeting ADAM9. Conclusion The novel style of stealth and MMP2-activated biomimetic nanoparticles show great potential in miRNA delivery. Supplementary Information The online version contains supplementary material available at 10.1186/s12943-022-01651-4.
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Affiliation(s)
- Lu Liang
- Guangzhou Municipal and Guangdong Provincial Key Laboratory of Molecular Target & Clinical Pharmacology, the NMPA and State Key Laboratory of Respiratory Disease, School of Pharmaceutical Sciences and the Fifth Affiliated Hospital, Guangzhou Medical University, Guangzhou, 511436, China
| | - Huiyu Cen
- Guangzhou Municipal and Guangdong Provincial Key Laboratory of Molecular Target & Clinical Pharmacology, the NMPA and State Key Laboratory of Respiratory Disease, School of Pharmaceutical Sciences and the Fifth Affiliated Hospital, Guangzhou Medical University, Guangzhou, 511436, China
| | - Jionghua Huang
- Guangzhou Municipal and Guangdong Provincial Key Laboratory of Molecular Target & Clinical Pharmacology, the NMPA and State Key Laboratory of Respiratory Disease, School of Pharmaceutical Sciences and the Fifth Affiliated Hospital, Guangzhou Medical University, Guangzhou, 511436, China.,Department of Cardiovascular Disease, The Third Affiliated Hospital, Guangzhou Medical University, Guangzhou, 510150, China
| | - Aiping Qin
- Guangzhou Municipal and Guangdong Provincial Key Laboratory of Molecular Target & Clinical Pharmacology, the NMPA and State Key Laboratory of Respiratory Disease, School of Pharmaceutical Sciences and the Fifth Affiliated Hospital, Guangzhou Medical University, Guangzhou, 511436, China
| | - Wenyan Xu
- Guangzhou Municipal and Guangdong Provincial Key Laboratory of Molecular Target & Clinical Pharmacology, the NMPA and State Key Laboratory of Respiratory Disease, School of Pharmaceutical Sciences and the Fifth Affiliated Hospital, Guangzhou Medical University, Guangzhou, 511436, China
| | - Siran Wang
- Department of Preventive Dentistry, Guangdong Engineering Research Center of Oral Restoration and Reconstruction, Guangzhou Key Laboratory of Basic and Applied Research of Oral Regenerative Medicine, Affiliated Stomatology Hospital of Guangzhou Medical University, 510182, Guangzhou, China
| | - Zhijun Chen
- Department of Medical Imaging, Affiliated Cancer Hospital & Institute of Guangzhou Medical University, Guangzhou, 510095, China
| | - Lin Tan
- Guangzhou Municipal and Guangdong Provincial Key Laboratory of Molecular Target & Clinical Pharmacology, the NMPA and State Key Laboratory of Respiratory Disease, School of Pharmaceutical Sciences and the Fifth Affiliated Hospital, Guangzhou Medical University, Guangzhou, 511436, China
| | - Qiqi Zhang
- Guangzhou Municipal and Guangdong Provincial Key Laboratory of Molecular Target & Clinical Pharmacology, the NMPA and State Key Laboratory of Respiratory Disease, School of Pharmaceutical Sciences and the Fifth Affiliated Hospital, Guangzhou Medical University, Guangzhou, 511436, China
| | - Xiyong Yu
- Guangzhou Municipal and Guangdong Provincial Key Laboratory of Molecular Target & Clinical Pharmacology, the NMPA and State Key Laboratory of Respiratory Disease, School of Pharmaceutical Sciences and the Fifth Affiliated Hospital, Guangzhou Medical University, Guangzhou, 511436, China.
| | - Xin Yang
- Guangzhou Municipal and Guangdong Provincial Key Laboratory of Molecular Target & Clinical Pharmacology, the NMPA and State Key Laboratory of Respiratory Disease, School of Pharmaceutical Sciences and the Fifth Affiliated Hospital, Guangzhou Medical University, Guangzhou, 511436, China.
| | - Lingmin Zhang
- Guangzhou Municipal and Guangdong Provincial Key Laboratory of Molecular Target & Clinical Pharmacology, the NMPA and State Key Laboratory of Respiratory Disease, School of Pharmaceutical Sciences and the Fifth Affiliated Hospital, Guangzhou Medical University, Guangzhou, 511436, China.
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miR-187/PDLIM1 Gets Involved in Gastric Cancer Progression and Cisplatin Sensitivity of Cisplatin by Mediating the Hippo-YAP Signaling Pathway. JOURNAL OF ONCOLOGY 2022; 2022:5456016. [PMID: 36164345 PMCID: PMC9509220 DOI: 10.1155/2022/5456016] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/27/2022] [Revised: 07/30/2022] [Accepted: 08/04/2022] [Indexed: 11/22/2022]
Abstract
Gastric cancer (GC) is one of the most prevalent malignancies in the digestive system across the world. The function and mechanism of PDLIM1, a cancer-suppressing gene, in gastric cancer progression remain unclear. This study is aimed at investigating the expression features and function of PDLIM1 in GC. RT-qPCR and western blot were used to compare the profiles of PDLIM1 and miR-187 between GC and normal tissues. The cell models of PDLIM1 overexpression and low expression were established in gastric cancer cell lines MKN45 and AGS. CCK8 and BrdU assays measured cell proliferation. Flow cytometry monitored cell apoptosis. Transwell analyzed cell invasion and migration. The influence of miR-187 overexpression on gastric cancer development was assessed. We predicted the targeted correlation between miR-187 and PDLIM1 through bioinformatics, which was corroborated via dual luciferase activity assay and RIP. Meanwhile, the cell model of PDLIM1 overexpression was built in AGS cells transfected with miR-187 mimics. A rescue experiment was conducted to assess the impact of PDLIM1 overexpression on the procancer function of miR-187. As a result, in contrast with normal paracancer tissues, PDLIM1 was substantially downregulated in GC tissues. Moreover, PDLIM1 overexpression considerably dampened proliferation, invasion, and migration in GC cells, boosted the cell apoptosis, and bolstered their sensitivity to cisplatin. PDLIM1 knockdown or miR-187 overexpression dramatically fostered GC cell proliferation, invasion, and migration and repressed cell apoptosis. Mechanism studies demonstrated that PDLIM1 vigorously restrained the profiles of the Hippo-YAP signaling pathway and the downstream target genes. miR-187 targeted PDLIM1, while miR-187 overexpression cramped PDLIM1 expression. The rescue experiment suggested that PDLIM1 overexpression weakened the procancer function of miR-187 in GC cells. In conclusion, our study demonstrated that PDLIM1 presented a low expression in GC tissues, while miR-187/PDLIM1 participated in GC development and cisplatin sensitivity by mediating the Hippo-YAP signaling pathway.
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A DCS-related lncRNA signature predicts the prognosis and chemotherapeutic response of patients with gastric cancer. Biosci Rep 2022; 42:231674. [PMID: 35993308 PMCID: PMC9446389 DOI: 10.1042/bsr20220989] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2022] [Revised: 08/10/2022] [Accepted: 08/19/2022] [Indexed: 11/21/2022] Open
Abstract
The combination of docetaxel, cisplatin, and S-1 (DCS) is a common chemotherapy regimen for patients with gastric cancer (GC). However, studies on long noncoding RNAs (lncRNAs) associated with the chemotherapeutic response to and prognosis after DCS remain lacking. The aim of the present study was to identify DCS mRNAs-lncRNAs associated with chemotherapy response and prognosis in GC patients. In the present study, we identified 548 lncRNAs associated with these 16 mRNAs in the TCGA and GSE31811 datasets. Eleven lncRNAs were used to construct a prognostic signature by least absolute shrinkage and selection operator (LASSO) regression. A model including the 11 lncRNAs (LINC02532, AC007277.1, AC005324.4, AL512506.1, AC068790.7, AC022509.2, AC113139.1, LINC00106, AC005165.1, MIR100HG, and UBE2R2-AS1) associated with the prognosis of GC was constructed. The signature was validated in the TCGA database, model comparison, and qRT-PCR experiments. The results showed that the risk signature was a more effective prognostic factor for GC patients. Furthermore, the results showed that this model can well predicting chemotherapy drug response and immune infiltration of GC patients. In addition, our experimental results indicated that lower expression levels of LINC00106 and UBE2R2-AS1 predicted worse drug resistance in AGS/DDP cells. The experimental results agreed with the predictions. Furthermore, knockdown of LINC00106 or UBE2R2-AS1 can significantly enhanced the proliferation and migration of GC AGS cells in vitro. In conclusion, a novel DCS therapy-related lncRNA signature may become a new strategy to predict chemotherapy response and prognosis in GC patients. LINC00106 and UBE2R2-AS1 may exhibit a tumor suppressive function in GC.
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Cheng Z, Guo Y, Sun J, Zheng L. Four-copy number alteration (CNA)-related lncRNA prognostic signature for liver cancer. Sci Rep 2022; 12:14261. [PMID: 35995822 PMCID: PMC9395537 DOI: 10.1038/s41598-022-17927-0] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2022] [Accepted: 08/02/2022] [Indexed: 11/26/2022] Open
Abstract
The objective of this study was to identify CNA-related lncRNAs that can better evaluate the prognosis of patients with liver cancer. Prognostic molecular subtypes were identified, followed by tumor mutation and differential expression analyses. Genomic copy number anomalies and their association with lncRNAs were also evaluated. A risk model was built based on lncRNAs, as well as a nomogram, and the differences in the tumor immune microenvironment and drug sensitivity between the High_ and Low_risk groups were compared. Weighted gene co-expression network analysis was used to identify modules with significant enrichment in prognostic-related lncRNAs. In total, two subtypes were identified, TP53 and CTNNB1 were common high-frequency mutated genes in the two subtypes. A total of 8,372 differentially expressed (DE) mRNAs and 798 DElncRNAs were identified between cluster1 and cluster2. In addition, a four-lncRNA signature was constructed, and statistically significant differences between the Low_ and High_risk groups were found in terms of CD8 T cells, resting memory CD4 T cells, etc. Enrichment analysis showed that prognostic-related lncRNAs were involved in the cell cycle, p53 signaling pathway, non-alcoholic fatty liver disease, etc. A prognostic prediction signature, based on four-CNA-related lncRNAs, could contribute to a more accurate prognosis of patients with liver cancer.
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Affiliation(s)
- Zhenyun Cheng
- Department of Clinical Laboratory, The First Affiliated Hospital of Zhengzhou University, No. 1 Jian She East Road, Zhengzhou, Henan, People's Republic of China, 450052.,Key Clinical Laboratory of Henan Province, NO.1 Jian She East Road, Zhengzhou, Henan, People's Republic of China, 450052
| | - Yan Guo
- Department of Clinical Laboratory, The First Affiliated Hospital of Zhengzhou University, No. 1 Jian She East Road, Zhengzhou, Henan, People's Republic of China, 450052.,Key Clinical Laboratory of Henan Province, NO.1 Jian She East Road, Zhengzhou, Henan, People's Republic of China, 450052
| | - Jingjing Sun
- Department of Clinical Laboratory, The First Affiliated Hospital of Zhengzhou University, No. 1 Jian She East Road, Zhengzhou, Henan, People's Republic of China, 450052.,Key Clinical Laboratory of Henan Province, NO.1 Jian She East Road, Zhengzhou, Henan, People's Republic of China, 450052
| | - Lei Zheng
- Department of Clinical Laboratory, The First Affiliated Hospital of Zhengzhou University, No. 1 Jian She East Road, Zhengzhou, Henan, People's Republic of China, 450052. .,Key Clinical Laboratory of Henan Province, NO.1 Jian She East Road, Zhengzhou, Henan, People's Republic of China, 450052.
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Zamani M, Foroughmand AM, Hajjari MR, Bakhshinejad B, Johnson R, Galehdari H. CASC11 and PVT1 spliced transcripts play an oncogenic role in colorectal carcinogenesis. Front Oncol 2022; 12:954634. [PMID: 36052265 PMCID: PMC9424822 DOI: 10.3389/fonc.2022.954634] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2022] [Accepted: 07/18/2022] [Indexed: 11/13/2022] Open
Abstract
Cancer is fundamentally a genetic disorder that alters cellular information flow toward aberrant growth. The coding part accounts for less than 2% of the human genome, and it has become apparent that aberrations within the noncoding genome drive important cancer phenotypes. The numerous carcinogenesis-related genomic variations in the 8q24 region include single nucleotide variations (SNVs), copy number variations (CNVs), and viral integrations occur in the neighboring areas of the MYC locus. It seems that MYC is not the only target of these alterations. The MYC-proximal mutations may act via regulatory noncoding RNAs (ncRNAs). In this study, gene expression analyses indicated that the expression of some PVT1 spliced linear transcripts, CircPVT1, CASC11, and MYC is increased in colorectal cancer (CRC). Moreover, the expression of these genes is associated with some clinicopathological characteristics of CRC. Also, in vitro studies in CRC cell lines demonstrated that CASC11 is mostly detected in the nucleus, and different transcripts of PVT1 have different preferences for nuclear and cytoplasmic parts. Furthermore, perturbation of PVT1 expression and concomitant perturbation in PVT1 and CASC11 expression caused MYC overexpression. It seems that transcription of MYC is under regulatory control at the transcriptional level, i.e., initiation and elongation of transcription by its neighboring genes. Altogether, the current data provide evidence for the notion that these noncoding transcripts can significantly participate in the MYC regulation network and in the carcinogenesis of colorectal cells.
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Affiliation(s)
- Mina Zamani
- Department of Biology, Faculty of Science, Shahid Chamran University of Ahvaz, Ahvaz, Iran
| | | | - Mohammad-Reza Hajjari
- Department of Biology, Faculty of Science, Shahid Chamran University of Ahvaz, Ahvaz, Iran
| | - Babak Bakhshinejad
- Department of Genetics, Faculty of Biological Sciences, Tarbiat Modares University, Tehran, Iran
| | - Rory Johnson
- Department of Medical Oncology, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland
- Department for BioMedical Research, University of Bern, Bern, Switzerland
- School of Biology and Environmental Science, University College Dublin, Dublin, Ireland
- Conway Institute for Biomolecular and Biomedical Research, University College Dublin, Dublin, Ireland
| | - Hamid Galehdari
- Department of Biology, Faculty of Science, Shahid Chamran University of Ahvaz, Ahvaz, Iran
- *Correspondence: Hamid Galehdari,
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Zhang H, Liu X, Liu Y, Liu J, Gong X, Li G, Tang M. Crosstalk between regulatory non-coding RNAs and oxidative stress in Parkinson’s disease. Front Aging Neurosci 2022; 14:975248. [PMID: 36016854 PMCID: PMC9396353 DOI: 10.3389/fnagi.2022.975248] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2022] [Accepted: 07/11/2022] [Indexed: 11/13/2022] Open
Abstract
Parkinson’s disease is the second most common neurodegenerative disease after Alzheimer’s disease, which imposes an ever-increasing burden on society. Many studies have indicated that oxidative stress may play an important role in Parkinson’s disease through multiple processes related to dysfunction or loss of neurons. Besides, several subtypes of non-coding RNAs are found to be involved in this neurodegenerative disorder. However, the interplay between oxidative stress and regulatory non-coding RNAs in Parkinson’s disease remains to be clarified. In this article, we comprehensively survey and overview the role of regulatory ncRNAs in combination with oxidative stress in Parkinson’s disease. The interaction between them is also summarized. We aim to provide readers with a relatively novel insight into the pathogenesis of Parkinson’s disease, which would contribute to the development of pre-clinical diagnosis and treatment.
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Affiliation(s)
- Hantao Zhang
- School of Life Sciences, Jiangsu University, Zhenjiang, China
| | - Xiaoyan Liu
- School of Life Sciences, Jiangsu University, Zhenjiang, China
| | - Yi Liu
- School of Life Sciences, Jiangsu University, Zhenjiang, China
- Institute of Animal Husbandry, Jiangsu Academy of Agricultural Sciences, Nanjing, China
| | - Junlin Liu
- School of Life Sciences, Jiangsu University, Zhenjiang, China
| | - Xun Gong
- Department of Rheumatology & Immunology, Affiliated Hospital of Jiangsu University, Zhenjiang, China
| | - Gang Li
- Department of Vascular Surgery, The Second Affiliated Hospital of Shandong First Medical University, Taian, China
- *Correspondence: Gang Li Min Tang
| | - Min Tang
- School of Life Sciences, Jiangsu University, Zhenjiang, China
- *Correspondence: Gang Li Min Tang
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Jiang L, Yang L, Dai Y, Yang G, Pan S. Expression of POT1-AS1 in GC Tissue, Its Effect on Biological Behavior of Gastric Cancer, and Its Significance on Prognosis of Gastric Cancer. COMPUTATIONAL AND MATHEMATICAL METHODS IN MEDICINE 2022; 2022:6021994. [PMID: 35936358 PMCID: PMC9355756 DOI: 10.1155/2022/6021994] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/24/2022] [Revised: 06/20/2022] [Accepted: 06/24/2022] [Indexed: 11/30/2022]
Abstract
Objective To study the correlation between gold in GC and biological indicators of gastric cancer (GC) and its effect on prognosis and correlation of POT1-AS1 with GC cellular growth, and to explore its impact in the processes of GC, to supply histological basis for medical treatment of GC. Methods From September 2019 to December 2021, 80 pairs of GAC specimens and healthy para-carcinoma tissue were immediately stored in paraformaldehyde solution. POT1-AS1 levels in 77 postoperative patients with GC were detected by immunohistochemical method. The correlation of the above indexes and the relationship between the above indexes and the biological behavior and prognosis of GC were analyzed. Results POT1-AS1 was strongly displayed in GAC specimens, and the difference between groups was statistically significant (P < 0.05). After sh-POT1-AS1 plasmid transfection, the relative expression of POT1-AS1 mRNA in SGC-7901 cells was remarkably lower compared to nontransfection group, and the difference between groups was statistically significant (P < 0.05). After POT1-AS1 knockdown, the SGC-7901 proliferation ability and the number of clones of SGC-7901 decreased remarkably. The relative level of cyclin D1 and cyclin-dependent kinase 4 (CDK4) in SGC-7901 reduced remarkably, while relative expression of cyclin-dependent kinase inhibitor 1A (CDKI1A) increased remarkably, and the difference between groups was statistically significant (P < 0.05). The positive expression of POT1-AS1 was found in GC and stromal cells. TIMP-1 in tumor stromal cells was related to the maximum diameter of tumor (P = 0.027), invasion depth (P = 0.001), lymph node metastasis (P = 0.006), and clinical stages (P = 0.006). TIMP-1 had an effect on the prognosis, while the strong positive group had a poor prognosis. The expression of TIMP-1 in GC cells was not related to clinical biological behavior and prognosis of GC. The VEGF level in GC was correlated to tumor maximum diameter (P < 0.05), invasive depth (P < 0.05), and lymph node metastasis (P < 0.05) that was linked to clinical phases, and the difference between groups was statistically significant (P < 0.05), which was positively correlated with Ki67-LI; the correlation coefficient was 0.254 and P = 0.026, which was not related to the positive expression of TIMP-1 in GC cells and stromal cells. VECF has an effect on the prognosis, and the outcomes of the positive group are worse. Conclusion The correlation between TIMP-1 of GASTRIC cancer mesenchymal cells of POT1-AS1 and VEGF and Ki-67-Li suggests that TIMP-1 produced by mesenchymal cells can facilitate tumor progression and lead to poor prognosis by promoting tumor cell proliferation. VEGF can strengthen tumor angiogenesis and then promote tumor cell proliferation, which has an adverse effect on the prognosis. Ki-67-LI is correlated to the medical biological behavior and prognosis of the tumor, reflecting the malignant process of the tumor.
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Affiliation(s)
- Li Jiang
- Department of Pathology, Liyang People's Hospital, 213300, China
| | - Lie Yang
- Department of Pathology, Liyang People's Hospital, 213300, China
| | - Yun Dai
- Department of Pathology, Liyang People's Hospital, 213300, China
| | - Guangming Yang
- Department of Pathology, Liyang People's Hospital, 213300, China
| | - Shuyin Pan
- Department of Pathology, Liyang People's Hospital, 213300, China
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Sun C, Chen Y, Kim NH, Lowe S, Ma S, Zhou Z, Bentley R, Chen YS, Tuason MW, Gu W, Bhan C, Tuason JPW, Thapa P, Cheng C, Zhou Q, Zhu Y. Identification and Verification of Potential Biomarkers in Gastric Cancer By Integrated Bioinformatic Analysis. Front Genet 2022; 13:911740. [PMID: 35910202 PMCID: PMC9337873 DOI: 10.3389/fgene.2022.911740] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2022] [Accepted: 06/08/2022] [Indexed: 12/13/2022] Open
Abstract
Background: Gastric cancer (GC) is a common cancer with high mortality. This study aimed to identify its differentially expressed genes (DEGs) using bioinformatics methods. Methods: DEGs were screened from four GEO (Gene Expression Omnibus) gene expression profiles. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were performed. A protein–protein interaction (PPI) network was constructed. Expression and prognosis were assessed. Meta-analysis was conducted to further validate prognosis. The receiver operating characteristic curve (ROC) was analyzed to identify diagnostic markers, and a nomogram was developed. Exploration of drugs and immune cell infiltration analysis were conducted. Results: Nine up-regulated and three down-regulated hub genes were identified, with close relations to gastric functions, extracellular activities, and structures. Overexpressed Collagen Type VIII Alpha 1 Chain (COL8A1), Collagen Type X Alpha 1 Chain (COL10A1), Collagen Triple Helix Repeat Containing 1 (CTHRC1), and Fibroblast Activation Protein (FAP) correlated with poor prognosis. The area under the curve (AUC) of ADAM Metallopeptidase With Thrombospondin Type 1 Motif 2 (ADAMTS2), COL10A1, Collagen Type XI Alpha 1 Chain (COL11A1), and CTHRC1 was >0.9. A nomogram model based on CTHRC1 was developed. Infiltration of macrophages, neutrophils, and dendritic cells positively correlated with COL8A1, COL10A1, CTHRC1, and FAP. Meta-analysis confirmed poor prognosis of overexpressed CTHRC1. Conclusion: ADAMTS2, COL10A1, COL11A1, and CTHRC1 have diagnostic values in GC. COL8A1, COL10A1, CTHRC1, and FAP correlated with worse prognosis, showing prognostic and therapeutic values. The immune cell infiltration needs further investigations.
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Affiliation(s)
- Chenyu Sun
- AMITA Health Saint Joseph Hospital Chicago, Chicago, IL, United States
| | - Yue Chen
- Department of Clinical Medicine, School of the First Clinical Medicine, Anhui Medical University, Hefei, China
| | - Na Hyun Kim
- AMITA Health Saint Joseph Hospital Chicago, Chicago, IL, United States
| | - Scott Lowe
- College of Osteopathic Medicine, Kansas City University, Kansas City, MO, United States
| | - Shaodi Ma
- Department of Epidemiology and Health Statistics, School of Public Health, Anhui Medical University, Hefei, China
| | - Zhen Zhou
- Menzies Institute for Medical Research, University of Tasmania, Hobart, TAS, Australia
| | - Rachel Bentley
- College of Osteopathic Medicine, Kansas City University, Kansas City, MO, United States
| | - Yi-Sheng Chen
- Department of Orthopedics, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | | | - Wenchao Gu
- Department of Diagnostic Radiology and Nuclear Medicine, Gunma University Graduate School of Medicine, Maebashi, Japan
| | - Chandur Bhan
- AMITA Health Saint Joseph Hospital Chicago, Chicago, IL, United States
| | | | - Pratikshya Thapa
- AMITA Health Saint Joseph Hospital Chicago, Chicago, IL, United States
| | - Ce Cheng
- The University of Arizona College of Medicine, Tucson, AZ, United States
- Banner-University Medical Center South, Tucson, AZ, United States
| | - Qin Zhou
- Mayo Clinic, Rochester, MN, United States
| | - Yanzhe Zhu
- Department of Oncology, The First Affiliated Hospital of Anhui Medical University, Hefei, China
- *Correspondence: Yanzhe Zhu,
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Identification of Novel Drugs Targeting Cell Cycle Regulators for the Treatment of High-Grade Serous Ovarian Cancer via Integrated Bioinformatics Analysis. Symmetry (Basel) 2022. [DOI: 10.3390/sym14071403] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/07/2022] Open
Abstract
High-grade serous ovarian carcinoma (HGSC), the most common and aggressive histological type of ovarian cancer, remains the leading cause of cancer-related deaths among females. It is important to develop novel drugs to improve the therapeutic outcomes of HGSC patients, thereby reducing their mortality. Symmetry is one of the most important properties of the biological network, which determines the stability of a biological system. As aberrant gene expression is a critical symmetry-breaking event that perturbs the stability of biological networks and triggers tumor progression, we aim in this study to discover new candidate drugs and predict their targets for HGSC therapy based on differentially expressed genes involved in HGSC pathogenesis. Firstly, 98 up-regulated genes and 108 down-regulated genes were identified from three independent transcriptome datasets. Then, the small-molecule compounds PHA-793887, pidorubicine and lestaurtinib, which target cell-cycle-related processes, were identified as novel candidate drugs for HGSC treatment by adopting the connectivity map (CMap)-based drug repositioning approach. Furthermore, through a topological analysis of the protein–protein interaction network, cell cycle regulators CDK1, TOP2A and AURKA were identified as bottleneck nodes, and their expression patterns were validated at the mRNA and protein expression levels. Moreover, the results of molecular docking analysis showed that PHA-793887, pidorubicine and lestaurtinib had a strong binding affinity for CDK1, TOP2A and AURKA, respectively. Therefore, our study repositioned PHA-793887, pidorubicine and lestaurtinib, which can inhibit cell cycle regulators, as novel agents for HGSC treatment, thereby helping to optimize the therapeutic strategy for HGSC.
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Chen YP, Wu HT, Hwang IE, Chen FF, Yao JY, Yin Y, Chen MY, Liaw LL, Kuo YC. Identification of the high-yield monacolin K strain from Monascus spp. and its submerged fermentation using different medicinal plants. BOTANICAL STUDIES 2022; 63:20. [PMID: 35779152 PMCID: PMC9250582 DOI: 10.1186/s40529-022-00351-y] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 03/09/2022] [Accepted: 06/25/2022] [Indexed: 06/15/2023]
Abstract
BACKGROUND Medical plants confer various benefits to human health and their bioconversion through microbial fermentation can increase efficacy, reduce toxicity, conserve resources and produce new chemical components. In this study, the cholesterol-lowering monacolin K genes and content produced by Monascus species were identified. The high-yield monacolin K strain further fermented with various medicinal plants. The antioxidant and anti-inflammatory activities, red pigment and monacolin K content, total phenolic content, and metabolites in the fermented products were analyzed. RESULTS Monacolin K was detected in Monascus pilosus (BCRC 38072), and Monascus ruber (BCRC 31533, 31523, 31534, 31535, and 33323). It responded to the highly homologous mokA and mokE genes encoding polyketide synthase and dehydrogenase. The high-yield monacolin K strain, M. ruber BCRC 31535, was used for fermentation with various medicinal plants. A positive relationship between the antioxidant capacity and total phenol content of the fermented products was observed after 60 days of fermentation, and both declined after 120 days of fermentation. By contrast, red pigment and monacolin K accumulated over time during fermentation, and the highest monacolin K content was observed in the fermentation of Glycyrrhiza uralensis, as confirmed by RT-qPCR. Moreover, Monascus-fermented medicinal plants including Paeonia lactiflora, Alpinia oxyphylla, G. uralensis, and rice were not cytotoxic. Only the product of Monascus-fermented G. uralensis significantly exhibited the anti-inflammatory capacity in a dose-dependent manner in lipopolysaccharide-induced Raw264.7 cells. The metabolites of G. uralensis with and without fermentation (60 days) were compared by LC/MS. 2,3-Dihydroxybenzoic acid, 3,4-dihydroxyphenylglycol, and 3-amino-4-hydroxybenzoate were considered to enhance the antioxidant and anti-inflammatory ability. CONCLUSIONS Given that highly homologous monacolin K and citrinin genes can be observed in Monascus spp., monacolin K produced by Monascus species without citrinin genes can be detected through the complementary methods of PCR and HPLC. In addition, the optimal fermentation time was important to the acquisition of antioxidants, red pigment and monacolin K. These bioactive substances were significantly affected by medicinal plants over fermentation time. Consequently, Monascus-fermented G. uralensis had a broad spectrum of biological activities.
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Affiliation(s)
- Yu-Pei Chen
- Department of Public Health and Medical Technology, Xiamen Medical College, Xiamen, 361023, Fujian, China
- Engineering Research Center of Natural Cosmeceuticals College of Fujian Province, Xiamen Medical College, Xiamen, 361023, Fujian, China
- Institute of Respiratory Diseases Xiamen Medical College, Xiamen Medical College, Xiamen, 361023, Fujian, China
| | - Hong-Tan Wu
- Department of Public Health and Medical Technology, Xiamen Medical College, Xiamen, 361023, Fujian, China
- Engineering Research Center of Natural Cosmeceuticals College of Fujian Province, Xiamen Medical College, Xiamen, 361023, Fujian, China
- Institute of Respiratory Diseases Xiamen Medical College, Xiamen Medical College, Xiamen, 361023, Fujian, China
| | - Ing-Er Hwang
- Bioresource Collection and Research Center, Food Industry Research and Development Institute, HsinChu, Taiwan
| | - Fang-Fang Chen
- Department of Public Health and Medical Technology, Xiamen Medical College, Xiamen, 361023, Fujian, China
- Engineering Research Center of Natural Cosmeceuticals College of Fujian Province, Xiamen Medical College, Xiamen, 361023, Fujian, China
| | - Jeng-Yuan Yao
- Institute of Respiratory Diseases Xiamen Medical College, Xiamen Medical College, Xiamen, 361023, Fujian, China
- Department of Basic Medicine, Xiamen Medical College, Xiamen, 361023, Fujian, China
| | - Yiling Yin
- Engineering Research Center of Natural Cosmeceuticals College of Fujian Province, Xiamen Medical College, Xiamen, 361023, Fujian, China
- Department of Medical Technology, Xiamen Medical College, Xiamen, 361023, Fujian, China
| | - Meng-Yun Chen
- Engineering Research Center of Natural Cosmeceuticals College of Fujian Province, Xiamen Medical College, Xiamen, 361023, Fujian, China
- Department of Medical Technology, Xiamen Medical College, Xiamen, 361023, Fujian, China
| | - Li-Ling Liaw
- Bioresource Collection and Research Center, Food Industry Research and Development Institute, HsinChu, Taiwan
| | - Yang-Cheng Kuo
- Bioresource Collection and Research Center, Food Industry Research and Development Institute, HsinChu, Taiwan.
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Chen X, Guo J, Zhou F, Ren W, Huang X, Pu J, Niu X, Jiang X. Long Non-Coding RNA AL139385.1 as a Novel Prognostic Biomarker in Lung Adenocarcinoma. Front Oncol 2022; 12:905871. [PMID: 35651789 PMCID: PMC9149219 DOI: 10.3389/fonc.2022.905871] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2022] [Accepted: 04/04/2022] [Indexed: 12/25/2022] Open
Abstract
Lung adenocarcinoma (LUAD) is the most common histological lung cancer, and it is the leading cause of cancer-related deaths worldwide. LncRNA-AL139385.1 (ENSG00000275880) is a novel lncRNA that is abnormally expressed in various cancer types including LUAD. However, the underlying biological function and potential mechanisms of AL139385.1 driving the progression of LUAD remain unclear. In this study, we investigated the role of AL139385.1 in LUAD and found that DNA hypomethylation was positively correlated with AL139385.1 expression in LUAD. Moreover, we uncover that the expression of AL139385.1 in LUAD tissues was significantly higher than that of AL139385.1 expression in adjacent normal tissues. Kaplan–Meier survival analysis showed that patients with higher AL139385.1 expression correlated with adverse overall survival and progression-free survival. Receiver operating characteristic (ROC) curve analysis showed that the area under the curve (AUC) value of AL139385.1 was 0.808. Correlation analysis showed that AL139385.1 expression was associated with immune infiltration in LUAD. We also found that AL139385.1 was upregulated in LUAD cancer tissues and cell lines. Knockdown of AL139385.1 significantly inhibited cell proliferation and migration abilities of LUAD. Finally, we constructed a ceRNA network that includes hsa-miR-532-5p and four mRNAs (GALNT3, CYCS, EIF5A, and ITGB4) specific to AL139385.1 in LUAD. Subsequent Kaplan–Meier survival analysis suggested that polypeptide N-acetylgalactosaminyltransferase 3 (GALNT3), cytochrome c, somatic (CYCS), eukaryotic translation initiation factor 5A (EIF5A), and integrin subunit beta 4 (ITGB4), were potential prognostic biomarkers for patients with LUAD. In conclusion, this finding provides possible mechanisms underlying the abnormal upregulation of AL139385.1 as well as a comprehensive view of the AL139385.1-mediated competing endogenous RNAs (ceRNA) network in LUAD, thereby highlighting its potential role in diagnosis and therapy.
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Affiliation(s)
- Xi Chen
- Department of Neurosurgery, The Second Affiliated Hospital of Kunming Medical University, Kunming, China
| | - Jishu Guo
- Institute for Ecological Research and Pollution Control of Plateau Lakes, School of Ecology and Environmental Science, Yunnan University, Kunming, China
| | - Fan Zhou
- Hematology and Rheumatology Department, The Pu'er People's Hospital, Pu'er, China
| | - Wenjun Ren
- Department of Cardiovascular Surgery, The First People's Hospital of Yunnan Province, Kunming, China
| | - Xiaobin Huang
- Department of Neurosurgery, The Second Affiliated Hospital of Kunming Medical University, Kunming, China
| | - Jun Pu
- Department of Neurosurgery, The Second Affiliated Hospital of Kunming Medical University, Kunming, China
| | - Xiaoqun Niu
- Department of Respiratory Medicine, Second Hospital of Kunming Medical University, Kunming, China
| | - Xiulin Jiang
- Kunming College of Life Science, University of Chinese Academy of Sciences, Beijing, China
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Ding R, Hong W, Huang L, Shao J, Yu W, Xu X. Examination of the effects of microRNA-145-5p and phosphoserine aminotransferase 1 in colon cancer. Bioengineered 2022; 13:12794-12806. [PMID: 35615948 PMCID: PMC9275947 DOI: 10.1080/21655979.2022.2071010] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
Previous studies manifested that microRNA-145-5p is pivotal in the development of various cancers. Nevertheless, the potential function of microRNA-145-5p in colorectal cancer remains unclear. This study attempted to investigate the potential role and possible mechanism of microRNA-145-5p in colon cancer. MicroRNA-145-5p and phosphoserine aminotransferase 1 (PSAT1) levels in colon cancer cells were assayed via quantitative reverse transcription polymerase chain reaction (qRT-PCR). Cell proliferation and cell cycle status were assessed using Cell Counting Kit-8, colony formation, and flow cytometry. The target binding relationship of microRNA-145-5p and PSAT1 was identified using bioinformatics analysis and dual-luciferase reporter gene assay. The result of qRT-PCR disclosed that microRNA-145-5p was markedly down-regulated and PSAT1 level was up-regulated in colon cancer cell lines. Besides, enforced microRNA-145-5p level repressed proliferation of colon cancer cells, and cells were arrested in G0-G1 phase. Bioinformatics analysis and dual-luciferase reporter genes confirmed that PSAT1 was a downstream target of microRNA-145-5p. Enforced PSAT1 level remarkably modulated cell cycle and fostered cell proliferation. Furthermore, rescue experiments displayed that microRNA-145-5p restrained cell cycle progression and cell proliferation and forced PSAT1 level could partially reverse this process. Taken together, our findings demonstrated that microRNA-145-5p repressed colon cancer cell cycle progression and cell proliferation via targeting PSAT1. Our findings identified microRNA-145-5p as an essential tumor repressor gene in colon cancer and may provide a novel biomarker for colon cancer.
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Affiliation(s)
- Ruliang Ding
- Department of Anorectal Surgery, Taizhou First People's Hospital, Taizhou, Zhejiang Province, China
| | - Weiwen Hong
- Department of Anorectal Surgery, Taizhou First People's Hospital, Taizhou, Zhejiang Province, China
| | - Liang Huang
- Department of Anorectal Surgery, Taizhou First People's Hospital, Taizhou, Zhejiang Province, China
| | - Jinfan Shao
- Department of Anorectal Surgery, Taizhou First People's Hospital, Taizhou, Zhejiang Province, China
| | - Wenfeng Yu
- Department of Anorectal Surgery, Taizhou First People's Hospital, Taizhou, Zhejiang Province, China
| | - Xijuan Xu
- Department of Anorectal Surgery, Taizhou First People's Hospital, Taizhou, Zhejiang Province, China
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Jin X, Shao X, Pang W, Wang Z, Huang J. Sex-determining Region Y-box transcription factor 13 promotes breast cancer cell proliferation and glycolysis by activating the tripartite motif containing 11-mediated Wnt/β-catenin signaling pathway. Bioengineered 2022; 13:13033-13044. [PMID: 35611828 PMCID: PMC9276007 DOI: 10.1080/21655979.2022.2073127] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Abstract
Breast cancer is the most frequent cancer among women and the second highest mortality in female across the world. Recent studies have illustrated that sex-determining region Y (SRY)-box protein (SOX) family plays essential roles in regulating various cancers. Nevertheless, the detailed effects of SOX13 on breast cancer are still uncovered. In our present study, SOX13 protein level was measured by using western blot assay in tissues and cells, and the results showed that SOX13 was upregulated in breast cancer tissues and cells compared with normal samples. Moreover, silencing SOX13 inhibited breast cancer cell viability, arrested cell cycle at G1/S phase and suppressed glycolysis, while overexpression of SOX13 reversed these events. Additionally, SOX13 knockdown reduced the level of proteins related to Wnt/β-catenin signaling pathway, whereas overexpression of tripartite motif containing 11 (TRM11) efficiently attenuated the effects, indicating that SOX13 controlled Wnt/β-catenin pathway depending on TRIM11. Furthermore, the data gained from xenograft tumor model illustrated that silencing SOX13 suppressed the tumor growth in nude mice and the glycolysis of tissues. In conclusion, our investigation illustrated that SOX13 facilitated breast cancer cell proliferation and glycolysis by modulating Wnt/β-catenin signaling pathway affected via TRIM11.
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Affiliation(s)
- Xiaoyan Jin
- Department of Breast Surgery, Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, Zhejiang Province, China.,Department of Breast Surgery, Taizhou Municipal Hospital, Taizhou, Zhejiang Province, China
| | - Xuan Shao
- Department of Breast Surgery, Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, Zhejiang Province, China
| | - Wenyang Pang
- Department of Breast Surgery, Taizhou Municipal Hospital, Taizhou, Zhejiang Province, China
| | - Zhengyi Wang
- Department of Breast Surgery, Taizhou Municipal Hospital, Taizhou, Zhejiang Province, China
| | - Jian Huang
- Department of Breast Surgery, Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, Zhejiang Province, China
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Chen Z, Tang W, Ye W, Song L, Chen Z. ADAMTS9-AS2 regulates PPP1R12B by adsorbing miR-196b-5p and affects cell cycle-related signaling pathways inhibiting the malignant process of esophageal cancer. Cell Cycle 2022; 21:1710-1725. [PMID: 35503407 PMCID: PMC9302527 DOI: 10.1080/15384101.2022.2067675] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/03/2022] Open
Abstract
This study explored the mechanism that ADAMTS9-AS2/miR-196b-5p/PPP1R12B/cell cycle pathway axis in inhibiting the malignant progression of esophageal cancer (EC), providing a new idea for targeted molecular therapy of EC. The expression data of EC tissue were acquired from TCGA database. The target lncRNA, downstream miRNA and its target gene were determined by bioinformatics analysis. ADAMTS9-AS2, miR-196b-5p and PPP1R12B levels in EC tissue and cells were assayed through qRT-PCR. Western blot was applied to assess protein level of PPP1R12B in cells and tissues, as well as protein expression of CDK1, cyclin A2, cyclin B1 and Plk1 in EC cells. Cell proliferation was assayed via CCK-8 assay. Cell cycle distribution was analyzed by flow cytometry. Cell migratory and invasive abilities were measured through scratch healing and transwell assays. Pearson correlation analysis was utilized to analyze relationship among ADAMTS9-AS2, miR-196b-5p and PPP1R12B. RIP was introduced to assess binding among the three. Dual-luciferase assay was utilized to verify targeted binding sites. The tumor formation in nude mice assay was utilized to detect tumorigenesis of EC cells in vivo. ADAMTS9-AS2 was significantly lowly expressed while miR-196b-5p was increased in EC tissue and cells. ADAMTS9-AS2 bound to miR-196b-5p and constrained its expression. Overexpressed ADAMTS9-AS2 inhibited EC cell malignant progression via downregulating miR-196b-5p, while overexpressed miR-196b-5p reversed this inhibitory effect. ADAMTS9-AS2 modulated PPP1R12B level by competitively inhibiting miR-196b-5p. PPP1R12B played a modulatory role in EC by inhibiting cell cycle pathway. Overexpressed ADAMTS9-AS2 regulated the tumor-forming ability of EC cells in vivo through miR-196b-5p/PPP1R12B/cell cycle signaling pathway axis. ADAMTS9-AS2 downregulated PPP1R12B by adsorbing miR-196b-5p, so as to regulate the cell cycle signaling pathway to inhibit EC malignant progression.
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Affiliation(s)
- Zhao Chen
- Department of Thoracic Surgery, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang Province, China
| | - Weijian Tang
- Department of Thoracic Surgery, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang Province, China
| | - Weiwen Ye
- Department of Thoracic Surgery, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang Province, China
| | - Lijiang Song
- Department of Thoracic Surgery, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang Province, China
| | - Zhoumiao Chen
- Department of Thoracic Surgery, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang Province, China
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