A c-Myc-MicroRNA functional feedback loop affects hepatocarcinogenesis.

Han Han, Dan Sun, Wenjuan Li, Hongxing Shen, Yahui Zhu, Chen Li, Yuxing Chen, Longfeng Lu, Wenhua Li, Jinxiang Zhang, Yuan Tian, Youjun Li

College of Life Sciences, State Key Laboratory of Virology, Wuhan University, Wuhan, China.

Hepatology (Baltimore, Md.) 2013 Jun

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c-Myc (Myc) plays an important role in normal liver development and tumorigenesis. We show here that Myc is pathologically activated in and essential for promoting human hepatocellular carcinoma (HCC). Myc induces HCC through a novel, microRNA (miRNA)-mediated feedback loop comprised of miR-148a-5p, miR-363-3p, and ubiquitin-specific protease 28 (USP28). Myc directly binds to conserved regions in the promoters of the two miRNAs and represses their expression. miR-148a-5p directly targets and inhibits Myc, whereas miR-363-3p destabilizes Myc by directly targeting and inhibiting USP28. Inhibition of miR-148a-5p or miR-363-3p induces hepatocellular tumorigenesis by promoting G1 to S phase progression, whereas activation of them has the opposite effects. The Myc-miRNA feedback loop is dysregulated in human HCC. Conclusion: These results define miR-148a-5p and miR-363-3p as negative regulators of Myc, thus revealing their heretofore unappreciated roles in hepatocarcinogenesis. (HEPATOLOGY 2013;57:2378-2389). Copyright © 2013 American Association for the Study of Liver Diseases.

Citation

Han Han, Dan Sun, Wenjuan Li, Hongxing Shen, Yahui Zhu, Chen Li, Yuxing Chen, Longfeng Lu, Wenhua Li, Jinxiang Zhang, Yuan Tian, Youjun Li. A c-Myc-MicroRNA functional feedback loop affects hepatocarcinogenesis. Hepatology (Baltimore, Md.). 2013 Jun;57(6):2378-89