title: The stem cell E3-ligase Lin-41 promotes liver cancer progression through inhibition of microRNA-mediated gene silencing.
abstract: Lin-41 is a stem cell-specific E3 ligase and a known target of the tumour suppressor microRNA (miRNA) let-7. Lin-41 was recently reported to mediate ubiquitylation and degradation of the miRNA pathway protein Ago2. We demonstrate that Lin-41 is over-expressed in hepatocellular carcinoma (HCC). Lin-41 over-expression correlates with high α-fetoprotein level, high tumour grade and high tumour stage and predicts early tumour recurrence. Lin-41 is a strong predictor of poor long-term survival for patients with HCC. Lin-41 knock-down by RNA interference in HCC cell lines Huh7 and Hep3B suppressed proliferation in vitro and reduced in vivo tumour growth in NOD/SCID mice. On the other hand, over-expression of Lin-41 in the HCC cell line SK-Hep1 enhanced tumourigenicity. Over-expression and knock-down of Lin-41 led to inverse changes in the levels of Ago1 and Ago2 proteins. Over-expression of Ago1 and Ago2 reduced in vivo tumour growth. Lin-41 over-expression suppressed let-7 activity in HCC cell lines and expression of Lin-41 enhanced the expression of let-7-regulated oncogenes c-Myc, Lin-28B, HMGA2 and type 1 insulin-like growth factor receptor (IGF1R). Expression of Lin-28B and c-Myc enhanced the expression of Lin-41. Chromatin immunoprecipitation and reporter assays revealed direct association of c-Myc with the Lin-41 promoter, resulting in transcriptional transactivation. Our results indicate that Lin-41 plays an important role in the growth of HCC by regulating RISC complex proteins Ago1 and Ago2 to inhibit miRNA-mediated gene silencing and promote the expression of oncogenic proteins. Lin-41 is also a strong prognostic factor for patients with HCC.
authors.affiliation: Graduate Institute of Pathology, National Taiwan University Hospital, 7 Chung-Shan South Road, Taipei, Taiwan.
authors.forename: Yu-Ling
authors.initials: YL
authors.lastname: Chen
authors.forename: Ray-Hwang
authors.initials: RH
authors.lastname: Yuan
authors.forename: Wan-Ching
authors.initials: WC
authors.lastname: Yang
authors.forename: Hey-Chi
authors.initials: HC
authors.lastname: Hsu
authors.forename: Yung-Ming
authors.initials: YM
authors.lastname: Jeng
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics*; D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D060565:Argonaute Proteins / Q000378:metabolism; D006528:Carcinoma, Hepatocellular / Q000175:diagnosis* / Q000235:genetics; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D018450:Disease Progression; D039642:Eukaryotic Initiation Factors / Q000378:metabolism; D005260:Female; D020868:Gene Silencing / Q000502:physiology*; D006801:Humans; D008113:Liver Neoplasms / Q000175:diagnosis* / Q000235:genetics; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D035683:MicroRNAs / Q000235:genetics*; D008875:Middle Aged; D014411:Neoplastic Stem Cells / Q000378:metabolism / Q000473:pathology*; D055815:Young Adult
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C549050:Ago1 protein, mouse; C526735:Ago2 protein, mouse; D060565:Argonaute Proteins; D039642:Eukaryotic Initiation Factors; D008565:Membrane Proteins; D035683:MicroRNAs; C114030:TRAT1 protein, human; C487931:mirnlet7 microRNA, human