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MicroRNAs (miRNAs) are key post-transcriptional regulators of gene expression and commonly deregulated in carcinogenesis. To explore functionally crucial tumor-suppressive (TS)-miRNAs in hepatocellular carcinoma (HCC), we performed integrative function- and expression-based screenings of TS-miRNAs in six HCC cell lines. The screenings identified seven miRNAs, which showed growth-suppressive activities through the overexpression of each miRNA and were endogenously downregulated in HCC cell lines. Further expression analyses using a large panel of HCC cell lines and primary tumors demonstrated four miRNAs,  miR-101 ,  -195 , - 378  and  -497 , as candidate TS-miRNAs frequently silenced in HCCs. Among them, two clustered miRNAs  miR-195  and  miR-497  showed significant growth-suppressive activity with induction of G1 arrest. Comprehensive exploration of their targets using Argonute2-immunoprecipitation-deep-sequencing (Ago2-IP-seq) and genome-wide expression profiling after their overexpression followed by pathway analysis, revealed a significant enrichment of cell cycle regulators. Among the candidates, we successfully identified  CCNE1 ,  CDC25A ,  CCND3 ,  CDK4 , and  BTRC  as direct targets for  miR-497  and  miR-195 . Moreover, target genes frequently upregulated in HCC in a tumor-specific manner, such as  CDK6 ,  CCNE1 ,  CDC25A  and  CDK4 , showed an inverse correlation in the expression of  miR-195  and  miR-497 , and their targets. These results suggest the molecular pathway regulating cell cycle progression to be integrally altered by downregulation of  miR-195  and  miR-497  expression, leading to the aberrant cell proliferation in hepatocarcinogenesis.

The Tumor-Suppressive miR-497-195 Cluster Targets Multiple Cell-Cycle Regulators in Hepatocellular Carcinoma