title: A c-Myc-MicroRNA functional feedback loop affects hepatocarcinogenesis.
abstract: 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.
  
  
  CONCLUSIONS
  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).
authors: College of Life Sciences, State Key Laboratory of Virology, Wuhan University, Wuhan, China.
authors: Han
authors: H
authors: Han
authors: Dan
authors: D
authors: Sun
authors: Wenjuan
authors: W
authors: Li
authors: Hongxing
authors: H
authors: Shen
authors: Yahui
authors: Y
authors: Zhu
authors: Chen
authors: C
authors: Li
authors: Yuxing
authors: Y
authors: Chen
authors: Longfeng
authors: L
authors: Lu
authors: Wenhua
authors: W
authors: Li
authors: Jinxiang
authors: J
authors: Zhang
authors: Yuan
authors: Y
authors: Tian
authors: Youjun
authors: Y
authors: Li
mesh_terms: D006528:Carcinoma, Hepatocellular / Q000209:etiology* / Q000378:metabolism; D059447:Cell Cycle Checkpoints; D002471:Cell Transformation, Neoplastic; D017124:Conserved Sequence; D018899:CpG Islands; D024721:E-Box Elements; D025461:Feedback, Physiological; D015972:Gene Expression Regulation, Neoplastic; D056945:Hep G2 Cells; D006801:Humans; D008113:Liver Neoplasms / Q000209:etiology* / Q000378:metabolism; D035683:MicroRNAs / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism*; D043222:Ubiquitin Thiolesterase / Q000378:metabolism
chemical_list: C550570:MIRN148 microRNA, human; C574861:MIRN363 microRNA, human; C489427:MYC protein, human; D035683:MicroRNAs; D016271:Proto-Oncogene Proteins c-myc; C442902:USP28 protein, human; D043222:Ubiquitin Thiolesterase