Original Research Article
Down-regulation of cyclin E1 expression by microrna-195 accounts for interferon-β-induced inhibition of hepatic stellate cell proliferation
Article first published online: 22 JUL 2011
Copyright © 2010 Wiley-Liss, Inc.
Journal of Cellular Physiology
Volume 226, Issue 10, pages 2535–2542, October 2011
How to Cite
Sekiya, Y., Ogawa, T., Iizuka, M., Yoshizato, K., Ikeda, K. and Kawada, N. (2011), Down-regulation of cyclin E1 expression by microrna-195 accounts for interferon-β-induced inhibition of hepatic stellate cell proliferation. J. Cell. Physiol., 226: 2535–2542. doi: 10.1002/jcp.22598
- Issue published online: 22 JUL 2011
- Article first published online: 22 JUL 2011
- Accepted manuscript online: 29 DEC 2010 11:41AM EST
- Manuscript Accepted: 3 DEC 2010
- Manuscript Received: 6 SEP 2010
- The Ministry of Health, Labour and Welfare of Japan. Grant Number: 2008-KAKEN-IPPAN-003
Recent studies have suggested that interferons (IFNs) have an antifibrotic effect in the liver independent of their antiviral effect although its detailed mechanism remains largely unknown. Some microRNAs have been reported to regulate pathophysiological activities of hepatic stellate cells (HSCs). We performed analyses of the antiproliferative effects of IFNs in HSCs with special regard to microRNA-195 (miR-195). We found that miR-195 was prominently down-regulated in the proliferative phase of primary-cultured mouse HSCs. Supporting this fact, IFN-β induced miR-195 expression and inhibited the cell proliferation by delaying their G1 to S phase cell cycle progression in human HSC line LX-2. IFN-β down-regulated cyclin E1 and up-regulated p21 mRNA levels in LX-2 cells. Luciferase reporter assay revealed the direct interaction of miR-195 with the cyclin E1 3′UTR. Overexpression of miR-195 lowered cyclin E1 mRNA and protein expression levels, increased p21 mRNA and protein expression levels, and inhibited cell proliferation in LX-2 cells. Moreover miR-195 inhibition restored cyclin E1 levels that were down-regulated by IFN-β. In conclusion, IFN-β inhibited the proliferation of LX-2 cells by delaying cell cycle progression in G1 to S phase, partially through the down-regulation of cyclin E1 and up-regulation of p21. IFN-induced miR-195 was involved in these processes. These observations reveal a new mechanistic aspect of the antifibrotic effect of IFNs in the liver. J. Cell. Physiol. 226: 2535–2542, 2011. © 2010 Wiley-Liss, Inc.