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Proc Natl Acad Sci U S A. 2018 Oct 30;115(44):E10417-E10426. doi: 10.1073/pnas.1808968115. Epub 2018 Oct 16.

Molecular profiling of nonalcoholic fatty liver disease-associated hepatocellular carcinoma using SB transposon mutagenesis.

Author information

1
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.
2
Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030.
3
Department of Molecular Oncology, Moffitt Cancer Center, Tampa, FL 33612.
4
Michigan Center for Translational Pathology, Department of Pathology, University of Michigan, Ann Arbor, MI 48109.
5
Department of Pathology, Texas Children's Hospital and Baylor College of Medicine, Houston, TX 77030.
6
Department of Obstetrics and Gynecology, Graduate School of Medicine, Osaka University, Osaka 5650871, Japan.
7
Cancer Research Program, Houston Methodist Research Institute, Houston, TX 77030.
8
Department of Gastroenterology and Hepatology, Graduate School of Medicine, Osaka University, Suita, Osaka 5650871, Japan.
9
Genetics Department, The University of Texas MD Anderson Cancer Center, Houston, TX 77030.
10
Genetics Department, The University of Texas MD Anderson Cancer Center, Houston, TX 77030 t-kodama@gh.med.osaka-u.ac.jp ncopeland1@mdanderson.org.

Abstract

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.

KEYWORDS:

Hippo; NAFLD; Sav1; Sleeping Beauty; liver cancer

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