These authors contributed equally to this work.
MicroRNA-494 within an oncogenic microRNA megacluster regulates G1/S transition in liver tumorigenesis through suppression of mutated in colorectal cancer
Article first published online: 22 NOV 2013
© 2013 Authors. Hepatology published by Wiley on behalf of the American Association for the Study of Liver Diseases
This is an open access article under the terms of the Creative Commons Attribution-NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.
Volume 59, Issue 1, pages 202–215, January 2014
How to Cite
Lim, L., Balakrishnan, A., Huskey, N., Jones, K. D., Jodari, M., Ng, R., Song, G., Riordan, J., Anderton, B., Cheung, S.-T., Willenbring, H., Dupuy, A., Chen, X., Brown, D., Chang, A. N. and Goga, A. (2014), MicroRNA-494 within an oncogenic microRNA megacluster regulates G1/S transition in liver tumorigenesis through suppression of mutated in colorectal cancer. Hepatology, 59: 202–215. doi: 10.1002/hep.26662
Potential conflict of interest: Nothing to report.
The work was supported by fellowship supported by A*STAR (to L.L.) and by the Susan G. Komen Foundation (to A.G.), the National Institutes of Health (CA136717 and CA170447; to A.G.), the University of California San Francisco (UCSF) Program for Breakthrough Biological Research and a V-Foundation award (to A.G.), and the UCSF Liver Center (P30 DK026743).
- Issue published online: 20 DEC 2013
- Article first published online: 22 NOV 2013
- Accepted manuscript online: 2 AUG 2013 06:57AM EST
- Manuscript Accepted: 26 JUL 2013
- Manuscript Received: 9 JAN 2013
Hepatocellular carcinoma (HCC) is associated with poor survival for patients and few effective treatment options, raising the need for novel therapeutic strategies. MicroRNAs (miRNAs) play important roles in tumor development and show deregulated patterns of expression in HCC. Because of the liver's unique affinity for small nucleic acids, miRNA-based therapy has been proposed in the treatment of liver disease. Thus, there is an urgent need to identify and characterize aberrantly expressed miRNAs in HCC. In our study, we profiled miRNA expression changes in de novo liver tumors driven by MYC and/or RAS, two canonical oncogenes activated in a majority of human HCCs. We identified an up-regulated miRNA megacluster comprised of 53 miRNAs on mouse chromosome 12qF1 (human homolog 14q32). This miRNA megacluster is up-regulated in all three transgenic liver models and in a subset of human HCCs. An unbiased functional analysis of all miRNAs within this cluster was performed. We found that miR-494 is overexpressed in human HCC and aids in transformation by regulating the G1/S cell cycle transition through targeting of the Mutated in Colorectal Cancer tumor suppressor. miR-494 inhibition in human HCC cell lines decreases cellular transformation, and anti-miR-494 treatment of primary MYC-driven liver tumor formation significantly diminishes tumor size. Conclusion: Our findings identify a new therapeutic target (miR-494) for the treatment of HCC. (Hepatology 2014;58:202–215)