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The stem cell E3‐ligase Lin‐41 promotes liver cancer progression through inhibition of microRNA‐mediated gene silencing

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. Copyright © 2012 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.