MicroRNA-195 suppresses tumorigenicity and regulates G1/S... : Hepatology (original) (raw)

Hepatobiliary Malignancies

MicroRNA-195 suppresses tumorigenicity and regulates G1/S transition of human hepatocellular carcinoma cells#

Xu, Teng1†; Zhu, Ying1†; Xiong, Yujuan1; Ge, Yi-Yuan1; Yun, Jing-Ping2,3; Zhuang, Shi-Mei1,2*‡

1 Key Laboratory of Gene Engineering of the Ministry of Education, State Key Laboratory of Biocontrol, School of Life Sciences

2 State Key Laboratory of Oncology in Southern China

3 Department of Pathology, Cancer Center, Sun Yat-sen University, Guangzhou, P.R. China

* Key Laboratory of Gene Engineering of the Ministry of Education, School of Life Sciences, Sun Yat-sen University, Xin Gang Xi Road 135#, Guangzhou 510275, P.R. China

Email:[email protected] or [email protected]

Received December 25, 2008; accepted February 12, 2009.

Published online 18 February 2009 in Wiley InterScience (www.interscience.wiley.com).

Grant sponsor: Ministry of Science and Technology of China; Grant Numbers: 2005CB724600 2007AA02Z124; Grant sponsor: National Natural Science Foundation of China; Grant Number: 30870964; Grant sponsor: Ministry of Health of China; Grant Number: 2008ZX10002-019.

# Potential conflict of interest: Nothing to report.

† These authors contributed equally to this work.

‡ fax: +86-20-84112169

Additional Supporting Information may be found in the online version of this article.

Abstract

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 G1/S transition, whereas inhibition of miR-195 promoted cell cycle progression. Subsequent investigation characterized multiple G1/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 G1 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 G1/S transition by repressing Rb-E2F signaling through targeting multiple molecules, including cyclin D1, CDK6, and E2F3. Conclusion: 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. (Hepatology 2009.)