miR-106b-25/miR-17-92 clusters: Polycistrons with oncogenic roles in hepatocellular carcinoma

MicroRNAs are small endogenously expressed RNA molecules which are involved in the process of silencing gene expression through translational regulation.The polycistronic miR-17-92 cluster is the first microRNA cluster shown to play a role in tumorigenesis.It has two other paralogs in the human genome,the miR-106b-25 cluster and the miR-106a-363 cluster.Collectively,the microRNAs encoded by these clusters can be further grouped based on the seed sequences into four families,namely the miR-17,the miR-92,the miR-18and the miR-19 families.Over-expression of the miR-106b-25 and miR-17-92 clusters has been reported not only during the development of cirrhosis but also subsequently during the development of hepatocellular carcinoma.Members of these clusters have also been shown to affect the replication of hepatitis B and hepatitis C viruses.Various targets of these microRNAs have been identified,and these targets are involved in tumor growth,cell survival and metastasis.In this review,we first describe the regulation of these clusters by c-Myc and E2F1,and how the members of these clusters inturn regulate E2F1 expression forming an auto-regulatory loop.In addition,the roles of the various members of the clusters in affecting relevant target gene expression in the pathogenesis of hepatocellular carcinoma will also be discussed.

Up-regulation of micro RNA-210 inhibits proliferation of hepatocellular carcinoma cells by targeting YES1

AIM: To determine the expression of micro RNA-210(mi R-210) in hepatocellular carcinoma(HCC) and to examine its role using HCC cells.METHODS: The expression of mi R-210 was determined in 21 pairs of HCC samples and the corresponding surrounding non-tumor tissues. The effects of mi R-210 on proliferation and cell cycle progression were examined using Hep G2 and Hu H7 cells. Overexpression and inhibition of mi R-210 was achieved by transfection of the cells with mi R-210 mimic or inhibitor. Luciferase reporter constructs were used to identify the mi R-210 interacting site on Yes1. Yes1 expression was examined after mi R-210 transfection,as well as in the HCC samples.RESULTS: mi R-210 was significantly up-regulated by 3.4 fold(P < 0.01) in the tumor samples. The over-expression of mi R-210 significantly reduced cell proliferation compared to the mock-treated cells(68.9% ± 7.4% and 53.6% ± 5.0%,P < 0.05 for the Hep G2 and Hu H7 cells respectively). Analysis of the Hu H7 cells transfected with mi R-210 mimic by flow cytometry showed that the cells took a longer time to reach the G2/M phase. The interaction between mi R-210 and the 3'UTR of the Yes1 transcript was confirmed using a luciferase reporter assay. Over-expression of mi R-210 reduced the expression of Yes1 protein in both Hu H7 and Hep G2 cells. Tumors with a greater than fourfold increase in the expression of mi R-210 showed consistently lower expressions of Yes1 in the tumors.In nocodazole-treated cells with a significant G2/M cell population,Yes1 protein was significantly reduced and pre-inhibition of mi R-210 in Hu H7 cells was able to prevent the reduction of Yes1 protein expression. Knock-down of Yes1 by si RNA also led to reduced cell proliferation(70.8% ± 7.5%,P < 0.05 in the Hu H7 cells).CONCLUSION: Up-regulation of mi R-210 inhibits cell proliferation. Yes1 is a target of mi R-210 and affects cell proliferation in HCC.