Rui Zhang1,2,3, Ying-Yi Jiang1,2,3, Kun Xiao4, Xiao-Quan Huang1,2,3, Jian Wang1,3, Shi-Yao Chen5,6,7,8. 1. Department of Gastroenterology and Hepatology, Zhongshan Hospital, Fudan University, 180 Fenglin Road, Shanghai, 200032, China. 2. Center of Evidence-Based Medicine, Fudan University, 180 Fenglin Road, Shanghai, 200032, China. 3. Shanghai Institute of Liver Disease, 180 Fenglin Road, Shanghai, 200032, China. 4. Department of Liver Surgery, Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, Liver Cancer Institute, Zhongshan Hospital, Fudan University, 180 Fenglin Road, Shanghai, 200032, China. 5. Department of Gastroenterology and Hepatology, Zhongshan Hospital, Fudan University, 180 Fenglin Road, Shanghai, 200032, China. chen.shiyao@zs-hospital.sh.cn. 6. Center of Evidence-Based Medicine, Fudan University, 180 Fenglin Road, Shanghai, 200032, China. chen.shiyao@zs-hospital.sh.cn. 7. Shanghai Institute of Liver Disease, 180 Fenglin Road, Shanghai, 200032, China. chen.shiyao@zs-hospital.sh.cn. 8. Endoscopy Center and Endoscopy Research Institute, Zhongshan Hospital, Fudan University, 180 Fenglin Road, Shanghai, 200032, China. chen.shiyao@zs-hospital.sh.cn.
Abstract
PURPOSE: This study aimed to explore the potential competing endogenous RNA (ceRNA) network in forecasting HCC development in patients with cirrhosis through a comprehensive bioinformatic analysis. METHODS: Data mining from GEO and TCGA databases was employed to dig a spectrum of differentially expressed mRNA, lncRNA and miRNA profiles. Their expression was confirmed by RT-PCR in matched HCC cohorts (n = 6/group). The ceRNA network was constructed by co-expression analysis. Their reciprocal regulations and their roles in epithelial-to-mesenchymal transition (EMT) process were validated by gain- and loss-of-function experiments at the cellular level. Kaplan-Meier method was applied to reveal prognostic values. RESULTS: By intersecting differentially expressed genes (DEGs) in GEO and TCGA data sets and Pearson correlation analysis, 20 mRNAs, 24 miRNAs and 41 lncRNAs were identified. Of these, FOXD2-AS1, BLVRA and CYTH2 were markedly upregulated in HCC tissues and HCC cells with high metastatic potential (MHCC97H) compared with their adjacent normal/cirrhotic tissues and L02 and MHCC97L cells. However, dysregulated miR-139-5p exhibited the opposite expression pattern. Using miRanda algorithms, FOXD2-AS1, BLVRA and CYTH2 showed potential binding sites for miR-139-5p. FOXD2-AS1 knockdown induced a marked increase in miR-139-5p and EMT inhibition. The loss of miR-139-5p led to an increase in BLVRA and CYTH2 expression and EMT process. Conversely, miR-139-5p overexpression suppressed BLVRA and CYTH expression and EMT process. FOXD2-AS1, miR-139-5p, BLVRA and CYTH2 highly correlated with prognosis in patients with HCC. CONCLUSION: FOXD2-AS1/miR-139-5p/BLVRA or CYTH2 axis might be the underlying molecular mechanism that dissects HCC development caused by cirrhosis.
PURPOSE: This study aimed to explore the potential competing endogenous RNA (ceRNA) network in forecasting HCC development in patients with cirrhosis through a comprehensive bioinformatic analysis. METHODS: Data mining from GEO and TCGA databases was employed to dig a spectrum of differentially expressed mRNA, lncRNA and miRNA profiles. Their expression was confirmed by RT-PCR in matched HCC cohorts (n = 6/group). The ceRNA network was constructed by co-expression analysis. Their reciprocal regulations and their roles in epithelial-to-mesenchymal transition (EMT) process were validated by gain- and loss-of-function experiments at the cellular level. Kaplan-Meier method was applied to reveal prognostic values. RESULTS: By intersecting differentially expressed genes (DEGs) in GEO and TCGA data sets and Pearson correlation analysis, 20 mRNAs, 24 miRNAs and 41 lncRNAs were identified. Of these, FOXD2-AS1, BLVRA and CYTH2 were markedly upregulated in HCC tissues and HCC cells with high metastatic potential (MHCC97H) compared with their adjacent normal/cirrhotic tissues and L02 and MHCC97L cells. However, dysregulated miR-139-5p exhibited the opposite expression pattern. Using miRanda algorithms, FOXD2-AS1, BLVRA and CYTH2 showed potential binding sites for miR-139-5p. FOXD2-AS1 knockdown induced a marked increase in miR-139-5p and EMT inhibition. The loss of miR-139-5p led to an increase in BLVRA and CYTH2 expression and EMT process. Conversely, miR-139-5p overexpression suppressed BLVRA and CYTH expression and EMT process. FOXD2-AS1, miR-139-5p, BLVRA and CYTH2 highly correlated with prognosis in patients with HCC. CONCLUSION:FOXD2-AS1/miR-139-5p/BLVRA or CYTH2 axis might be the underlying molecular mechanism that dissects HCC development caused by cirrhosis.
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