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Downregulated ZC3H13 by miR-362-3p/miR-425-5p is Associated with Poor Prognosis and Adverse Outcomes in Hepatocellular Carcinoma


 Background: Hepatocellular carcinoma (HCC) is notorious for its poor prognosis. Increasing evidence has demonstrated that N6-methyladenosine (m6A) related genes plays key roles in initiation and progression of several types of human cancer. However, the specific role and mechanism of m6A RNA modification in HCC remains not fully determined. Previous studies identified that several m6A-related genes, especially ZC3H13, could be a high candidate as a novel biomarker and therapeutic target for hepatocellular carcinoma. In liver hepatocellular carcinoma (LIHC), the low expression of ZC3H13 was reported but the molecular reason is unclear.Methods: Oncomine and GEPIA databases were used to explore the differential expression of ZC3H13 in multiple cancers. Kaplan–Meier plotter was selected to explore the prognostic value of ZC3H13. The GSCALite database was used to analyze the genetic variation of the m6A-related genes. StarBase was selected to predict and analysis of upstream miRNAs of ZC3H13. MiR-362-3p/miR-425-5p mimics and inhibitors results detected by Quantitative Real-time PCR (qPCR) analysis and western blotting. Gene set enrichment analysis (GSEA) identified the potential regulatory mechanism of ZC3H13. In addition, we investigated the relationship between ZC3H13 and tumor infiltrating immune cells (TIICs). Finally, we determined the expression correlation of ZC3H13 with biomarkers of immune cells in HCC using GEPIA database.Results: In this study, we found that ZC3H13 expression was significantly correlated with both overall survival (OS) and progression-free survival (RFS) in LIHC patients based on a comprehensive analysis of the m6A family. Our experimental results indicate that inhibiting miR-362-3p/miR-425-5p expression in the LIHC cell line significantly restored the expression of ZC3H13, which is consistent with bioinformatic studies. Further, we noticed that there is a possible relationship between ZC3H13 high expression and tumor microenvironment infiltrating immune cells.Conclusions: In conclusion, this study demonstrates that ZC3H13 is a direct target of miR-362-3p/miR-425-5p in LIHC that regulates the immune modulations in the microenvironment of LIHC.