PMID- 30327349 OWN - NLM STAT- MEDLINE DCOM- 20181212 LR - 20181212 IS - 1091-6490 (Electronic) IS - 0027-8424 (Print) IS - 0027-8424 (Linking) VI - 115 IP - 44 DP - 2018 Oct 30 TI - Molecular profiling of nonalcoholic fatty liver disease-associated hepatocellular carcinoma using SB transposon mutagenesis. PG - E10417-E10426 LID - 10.1073/pnas.1808968115 [doi] AB - Nonalcoholic fatty liver disease (NAFLD) is the fastest rising cause of hepatocellular carcinoma (HCC) in Western countries; however, the molecular mechanisms that cause NAFLD-HCC remain elusive. To identify molecular drivers of NAFLD-HCC, we performed Sleeping Beauty (SB) transposon mutagenesis screens in liver-specific Pten knockout and in high-fat diet-fed mice, which are murine models of NAFLD-HCC. SB mutagenesis accelerated liver tumor formation in both models and identified 588 and 376 candidate cancer genes (CCGs), respectively; 257 CCGs were common to both screens and were enriched in signaling pathways known to be important for human HCC. Comparison of these CCGs with those identified in a previous SB screen of hepatitis B virus-induced HCC identified a core set of 141 CCGs that were mutated in all screens. Forty-one CCGs appeared specific for NAFLD-HCC, including Sav1, a component of the Hippo signaling pathway and the most frequently mutated gene identified in both NAFLD-HCC screens. Liver-specific deletion of Sav1 was found to promote hepatic lipid accumulation, apoptosis, and fibrogenesis, leading to the acceleration of hepatocarcinogenesis in liver-specific Pten mutant mice. Sav1/Pten double-mutant livers also showed a striking up-regulation of markers of liver progenitor cells (LPCs), along with synergistic activation of Yap, which is a major downstream effector of Hippo signaling. Lastly, Yap activation, in combination with Pten inactivation, was found to accelerate cell growth and sphere formation of LPCs in vitro and induce their malignant transformation in allografts. Our forward genetic screens in mice have thus identified pathways and genes driving the development of NAFLD-HCC. CI - Copyright (c) 2018 the Author(s). Published by PNAS. FAU - Kodama, Takahiro AU - Kodama T AUID- ORCID: 0000-0002-6250-1324 AD - Department of Gastroenterology and Hepatology, Graduate School of Medicine, Osaka University, Suita, Osaka 5650871, Japan; t-kodama@gh.med.osaka-u.ac.jp ncopeland1@mdanderson.org. FAU - Yi, Jing AU - Yi J AD - Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030. FAU - Newberg, Justin Y AU - Newberg JY AD - Department of Molecular Oncology, Moffitt Cancer Center, Tampa, FL 33612. FAU - Tien, Jean C AU - Tien JC AD - Michigan Center for Translational Pathology, Department of Pathology, University of Michigan, Ann Arbor, MI 48109. FAU - Wu, Hao AU - Wu H AD - Department of Pathology, Texas Children's Hospital and Baylor College of Medicine, Houston, TX 77030. FAU - Finegold, Milton J AU - Finegold MJ AD - Department of Pathology, Texas Children's Hospital and Baylor College of Medicine, Houston, TX 77030. FAU - Kodama, Michiko AU - Kodama M AD - Department of Obstetrics and Gynecology, Graduate School of Medicine, Osaka University, Osaka 5650871, Japan. FAU - Wei, Zhubo AU - Wei Z AD - Cancer Research Program, Houston Methodist Research Institute, Houston, TX 77030. FAU - Tamura, Takeshi AU - Tamura T AD - Department of Gastroenterology and Hepatology, Graduate School of Medicine, Osaka University, Suita, Osaka 5650871, Japan. FAU - Takehara, Tetsuo AU - Takehara T AD - Department of Gastroenterology and Hepatology, Graduate School of Medicine, Osaka University, Suita, Osaka 5650871, Japan. FAU - Johnson, Randy L AU - Johnson RL AD - Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030. FAU - Jenkins, Nancy A AU - Jenkins NA AD - Genetics Department, The University of Texas MD Anderson Cancer Center, Houston, TX 77030. FAU - Copeland, Neal G AU - Copeland NG AD - Genetics Department, The University of Texas MD Anderson Cancer Center, Houston, TX 77030 t-kodama@gh.med.osaka-u.ac.jp ncopeland1@mdanderson.org. LA - eng PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't DEP - 20181016 PL - United States TA - Proc Natl Acad Sci U S A JT - Proceedings of the National Academy of Sciences of the United States of America JID - 7505876 RN - 0 (DNA Transposable Elements) SB - IM MH - Animals MH - Apoptosis/genetics MH - Carcinogenesis/genetics/pathology MH - Carcinoma, Hepatocellular/*genetics/*pathology MH - Cell Transformation, Neoplastic/genetics/pathology MH - DNA Transposable Elements/*genetics MH - Diet, High-Fat/adverse effects MH - Liver/pathology MH - Liver Neoplasms/*genetics/*pathology MH - Mice MH - Mutagenesis/genetics MH - Non-alcoholic Fatty Liver Disease/*genetics/*pathology MH - Oncogenes/genetics MH - Signal Transduction/genetics MH - Up-Regulation/genetics PMC - PMC6217425 OTO - NOTNLM OT - Hippo OT - NAFLD OT - Sav1 OT - Sleeping Beauty OT - liver cancer COIS- The authors declare no conflict of interest. EDAT- 2018/10/18 06:00 MHDA- 2018/12/13 06:00 PMCR- 2018/10/16 CRDT- 2018/10/18 06:00 PHST- 2018/10/18 06:00 [pubmed] PHST- 2018/12/13 06:00 [medline] PHST- 2018/10/18 06:00 [entrez] PHST- 2018/10/16 00:00 [pmc-release] AID - 1808968115 [pii] AID - 201808968 [pii] AID - 10.1073/pnas.1808968115 [doi] PST - ppublish SO - Proc Natl Acad Sci U S A. 2018 Oct 30;115(44):E10417-E10426. doi: 10.1073/pnas.1808968115. Epub 2018 Oct 16.