MicroRNA-195 suppresses tumorigenicity and regulates G1/S transition of human hepatocellular carcinoma cells.
Growing evidence indicates that deregulation of microRNAs (miRNAs) contributes to tumorigenesis. Down-regulation of miR-195 has been observed in various types of cancers. However, the biological function of miR-195 is still largely unknown. In this study we aimed to elucidate the pathophysiologic role of miR-195. Our results showed that miR-195 expression was significantly reduced in as high as 85.7% of hepatocellular carcinoma (HCC) tissues and in all of the five HCC cell lines examined. Moreover, introduction of miR-195 dramatically suppressed the ability of HCC and colorectal carcinoma cells to form colonies in vitro and to develop tumors in nude mice. Furthermore, ectopic expression of miR-195 blocked G(1)/S transition, whereas inhibition of miR-195 promoted cell cycle progression. Subsequent investigation characterized multiple G(1)/S transition-related molecules, including cyclin D1, CDK6, and E2F3, as direct targets of miR-195. Silencing of cyclin D1, CDK6, or E2F3 phenocopied the effect of miR-195, whereas overexpression of these proteins attenuated miR-195-induced G(1) arrest. In addition, miR-195 significantly repressed the phosphorylation of Rb as well as the transactivation of downstream target genes of E2F. These results imply that miR-195 may block the G(1)/S transition by repressing Rb-E2F signaling through targeting multiple molecules, including cyclin D1, CDK6, and E2F3.


CONCLUSIONS
Our data highlight an important role of miR-195 in cell cycle control and in the molecular etiology of HCC, and implicate the potential application of miR-195 in cancer therapy.
Xu
Teng
T
Key Laboratory of Gene Engineering of the Ministry of Education, State Key Laboratory of Biocontrol, School of Life Sciences, Guangzhou, PR China.
Zhu
Ying
Y
Xiong
Yujuan
Y
Ge
Yi-Yuan
YY
Yun
Jing-Ping
JP
Zhuang
Shi-Mei
SM
D006528:Carcinoma, Hepatocellular / Q000235:genetics*; D016147:Genes, Tumor Suppressor; D006801:Humans; D007399:Interphase; D008113:Liver Neoplasms / Q000235:genetics*; D035683:MicroRNAs / Q000502:physiology*; D014407:Tumor Cells, Cultured
D035683:MicroRNAs