ArticleProceedings of the National Academy of Sciences of the United States of America2018
Molecular profiling of nonalcoholic fatty liver disease-associated hepatocellular carcinoma using SB transposon mutagenesis.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 33 papers.
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Who cites it
33 citing papers in PubMed, 60 citations in OpenAlex.
- Etiology-Driven Mouse Models of Hepatocellular Carcinoma: Paving the Way for Precision Oncology.Journal of hepatocellular carcinoma · 2026Review
- A Mouse in vivo Model Mimicking MASH-Related HCC Pathogenesis.Journal of hepatocellular carcinoma · 2026Article
- Molecular mechanisms in MASLD/MASH-related HCC.Hepatology (Baltimore, Md.) · 2025Review
- Development of a whole-exome sequencing kit to facilitate porcine biomedical research.Genome biology · 2025Article
- Small-molecule-based targeted therapy in liver cancer.Molecular therapy : the journal of the American Society of Gene Therapy · 2024Review
- Molecular Genealogy of Metabolic-associated Hepatocellular Carcinoma.Seminars in liver disease · 2024Review
- Role of Hippo pathway dysregulation from gastrointestinal premalignant lesions to cancer.Journal of translational medicine · 2024Review
- Loss of the methylarginine reader function of SND1 confers resistance to hepatocellular carcinoma.The Biochemical journal · 2023Article
- RING finger protein 13 protects against nonalcoholic steatohepatitis by targeting STING-relayed signaling pathways.Nature communications · 2023Article
- Article
- Elevated Nuclear PHGDH Synergistically Functions with cMyc to Reshape the Immune Microenvironment of Liver Cancer.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2023Article
- Advances in transposable elements: from mechanisms to applications in mammalian genomics.Frontiers in genetics · 2023Review
- Hepatocyte Smoothened Activity Controls Susceptibility to Insulin Resistance and Nonalcoholic Fatty Liver Disease.Cellular and molecular gastroenterology and hepatology · 2023Article
- Article
- Transcriptomics Identify Thrombospondin-2 as a Biomarker for NASH and Advanced Liver Fibrosis.Hepatology (Baltimore, Md.) · 2021Article
- Exploring liver cancer biology through functional genetic screens.Nature reviews. Gastroenterology & hepatology · 2021Review
- Dysregulation of PI3K and Hippo signaling pathways synergistically induces chronic pancreatitis via CTGF upregulation.The Journal of clinical investigation · 2021Article
- Parthenolide plays a protective role in the liver of mice with metabolic dysfunction‑associated fatty liver disease through the activation of the HIPPO pathway.Molecular medicine reports · 2021Article
- The tumor suppressor role of salvador family WW domain-containing protein 1 (SAV1): one of the key pieces of the tumor puzzle.Journal of cancer research and clinical oncology · 2021Review
- Mechanisms by Which Probiotic Bacteria Attenuate the Risk of Hepatocellular Carcinoma.International journal of molecular sciences · 2021Review
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Authors and funding
13 authors at 6 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
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.
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