Supported by grants from the Ministry of Science and Technology of China (2010CB912803, 2011CB811305, 2011ZX09307-001-04), the Ministry of Health of China (2012ZX10002011), the National Natural Science Foundation of China (30925036, 81230049), and the Fundamental Research Funds for the Central Universities (12lgjc03, 12lgpy25).
MicroRNA-195 Suppresses Angiogenesis and Metastasis of Hepatocellular Carcinoma by Inhibiting the Expression of VEGF, VAV2, and CDC42
Article first published online: 29 JUL 2013
Copyright © 2013 by the American Association for the Study of Liver Diseases
Volume 58, Issue 2, pages 642–653, August 2013
How to Cite
Wang, R., Zhao, N., Li, S., Fang, J.-H., Chen, M.-X., Yang, J., Jia, W.-H., Yuan, Y. and Zhuang, S.-M. (2013), MicroRNA-195 Suppresses Angiogenesis and Metastasis of Hepatocellular Carcinoma by Inhibiting the Expression of VEGF, VAV2, and CDC42. Hepatology, 58: 642–653. doi: 10.1002/hep.26373
Potential conflict of interest: Nothing to report.
- Issue published online: 29 JUL 2013
- Article first published online: 29 JUL 2013
- Accepted manuscript online: 6 MAR 2013 05:22PM EST
- Manuscript Accepted: 26 FEB 2013
- Manuscript Revised: 7 FEB 2013
- Manuscript Received: 3 DEC 2012
Hepatocellular carcinoma (HCC) is characterized by active angiogenesis and metastasis, which account for rapid recurrence and poor survival. There is frequent down-regulation of miR-195 expression in HCC tissues. In this study, the role of miR-195 in HCC angiogenesis and metastasis was investigated with in vitro capillary tube formation and transwell assays, in vivo orthotopic xenograft mouse models, and human HCC specimens. Reduction of miR-195 in HCC tissues was significantly associated with increased angiogenesis, metastasis, and worse recurrence-free survival. Both gain-of-function and loss-of-function studies of in vitro models revealed that miR-195 not only suppressed the ability of HCC cells to promote the migration and capillary tube formation of endothelial cells but also directly repressed the abilities of HCC cells to migrate and invade extracellular matrix gel. Based on mouse models, we found that the induced expression of miR-195 dramatically reduced microvessel densities in xenograft tumors and repressed both intrahepatic and pulmonary metastasis. Subsequent investigations disclosed that miR-195 directly inhibited the expression of the proangiogenic factor vascular endothelial growth factor (VEGF) and the prometastatic factors VAV2 and CDC42. Knockdown of these target molecules of miR-195 phenocopied the effects of miR-195 restoration, whereas overexpression of these targets antagonized the function of miR-195. Furthermore, we revealed that miR-195 down-regulation resulted in enhanced VEGF levels in the tumor microenvironment, which subsequently activated VEGF receptor 2 signaling in endothelial cells and thereby promoted angiogenesis. Additionally, miR-195 down-regulation led to increases in VAV2 and CDC42 expression, which stimulated VAV2/Rac1/CDC42 signaling and lamellipodia formation and thereby facilitated the metastasis of HCC cells. Conclusion: miR-195 deregulation contributes to angiogenesis and metastasis in HCC. The restoration of miR-195 expression may be a promising strategy for HCC therapy. (Hepatology 2013;58:642-653)