Molecular profiling of nonalcoholic fatty liver diseaseassociated hepatocellular carcinoma using SB transposon mutagenesis

Takahiro Kodama, Jing Yi, Justin Y. Newberg, Jean C. Tien, Hao Wu, Milton J. Finegold, Michiko Kodama, Zhubo Wei, Takeshi Tamura, Tetsuo Takehara, Randy L. Johnson, Nancy A. Jenkins, Neal G. Copeland

Research output: Contribution to journalArticle

15 Scopus citations

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 liverspecific 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 virusinduced 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.

Original languageEnglish (US)
Pages (from-to)E10417-E10426
JournalProceedings of the National Academy of Sciences of the United States of America
Volume115
Issue number44
DOIs
StatePublished - Oct 30 2018

Keywords

  • Hippo
  • Liver cancer
  • NAFLD
  • Sav1
  • Sleeping Beauty

ASJC Scopus subject areas

  • General

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