These authors contributed equally to this study.
Article first published online: 7 JAN 2013
Copyright © 2012 American Association for the Study of Liver Diseases
Volume 57, Issue 1, pages 299–310, January 2013
How to Cite
Yuan, Q., Loya, K., Rani, B., Möbus, S., Balakrishnan, A., Lamle, J., Cathomen, T., Vogel, A., Manns, M. P., Ott, M., Cantz, T. and Sharma, A. D. (2013), MicroRNA-221 overexpression accelerates hepatocyte proliferation during liver regeneration. Hepatology, 57: 299–310. doi: 10.1002/hep.25984
Potential conflict of interest: Nothing to report.
Supported by grants from the German Research Foundation (EXC 62/1, SFB 738, SH640/1-1) and HiLF from Hannover Medical School. S.M. and B.R. receive stipends from the Hannover Biomedical Research School (HBRS).
- Issue published online: 7 JAN 2013
- Article first published online: 7 JAN 2013
- Accepted manuscript online: 23 JUL 2012 06:11AM EST
- Manuscript Accepted: 6 JUL 2012
- Manuscript Received: 11 APR 2012
The tightly controlled replication of hepatocytes in liver regeneration and uncontrolled proliferation of tumor cells in hepatocellular carcinoma (HCC) are often modulated by common regulatory pathways. Several microRNAs (miRNAs) are involved in HCC progression by modulating posttranscriptional expression of multiple target genes. miR-221, which is frequently up-regulated in HCCs, delays fulminant liver failure in mice by inhibiting apoptosis, indicating a pleiotropic role of miR-221 in hepatocytes. Here, we hypothesize that modulation of miR-221 targets in primary hepatocytes enhances proliferation, providing novel clues for enhanced liver regeneration. We demonstrate that miR-221 enhances proliferation of in vitro cultivated primary hepatocytes. Furthermore, applying two-thirds partial hepatectomy as a surgically induced liver regeneration model we show that adeno-associated virus-mediated overexpression of miR-221 in the mouse liver also accelerates hepatocyte proliferation in vivo. miR-221 overexpression leads to rapid S-phase entry of hepatocytes during liver regeneration. In addition to the known targets p27 and p57, we identify Aryl hydrocarbon nuclear translocator (Arnt) messenger RNA (mRNA) as a novel target of miR-221, which contributes to the pro-proliferative activity of miR-221. Conclusion: miR-221 overexpression accelerates hepatocyte proliferation. Pharmacological intervention targeting miR-221 may thus be therapeutically beneficial in liver failure by preventing apoptosis and by inducing liver regeneration. (HEPATOLOGY 2013;)