Hepatocyte-specific Pten deficiency results in steatohepatitis and hepatocellular carcinomas.

By Y. Horie, A. Suzuki, E. Kataoka, Takehiko Sasaki, K. Hamada, J. Sasaki, K. Mizuno, G. Hasegawa, H. Kishimoto, M. Iizuka and 5 more. Journal of Clinical Investigation, 2004

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PTEN is a tumor suppressor gene mutated in many human cancers, and its expression is reduced or absent in almost half of hepatoma patients. We used the Cre-loxP system to generate a hepatocyte-specific null mutation of Pten in mice (AlbCrePten(flox/flox) mice). AlbCrePten(flox/flox) mice showed massive hepatomegaly and steatohepatitis with triglyceride accumulation, a phenotype similar to human nonalcoholic steatohepatitis. Adipocyte-specific genes were induced in mutant hepatocytes, implying adipogenic-like transformation of these cells. Genes involved in lipogenesis and beta-oxidation were also induced, possibly as a result of elevated levels of the transactivating factors PPARgamma and SREBP1c. Importantly, the loss of Pten function in the liver led to tumorigenesis, with 47% of AlbCrePten(flox/flox) livers developing liver cell adenomas by 44 weeks of age. By 74-78 weeks of age, 100% of AlbCrePten(flox/flox) livers showed adenomas and 66% had hepatocellular carcinomas. AlbCrePten(flox/flox) mice also showed insulin hypersensitivity. In vitro, AlbCrePten(flox/flox) hepatocytes were hyperproliferative and showed increased hyperoxidation with abnormal activation of protein kinase B and MAPK. Pten is thus an important regulator of lipogenesis, glucose metabolism, hepatocyte homeostasis, and tumorigenesis in the liver.

Subfields: Molecular Biology, Surgery

View Paper: https://www.semanticscholar.org/paper/95e3ae273b61cc769990b8838de8e1881cf49b7e

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Citations in the corpus

PTEN loss in the continuum of common cancers, rare syndromes and mouse models (2011, neutral): “Tumours took longer to develop after Pten deletion in the live”
Nrf2 redirects glucose and glutamine into anabolic pathways in metabolic reprogramming. (2012, background): “Animals The generation of Nrf2 , Keap1 , Keap1, and Pten mice has been described (Itoh et al., 1997; Wakabayashi et al., 2003; Okawa et al., 2006; Horie et al., 2004).”
The Role of Cancer-Associated Fibroblasts and Fibrosis in Liver Cancer (2016, background): “Of note, the β-catenin, Hippo, and PTEN pathways are important contributors to hepatocarcinogenesis (16, 134, 135).”
CRISPR-mediated direct mutation of cancer genes in the mouse liver (2014, neutral): “Liver-specific knockout of Pten in mice induces lipid accumulation and late-onset liver cancer 7, 8 .”
Lipid metabolism and liver inflammation. II. Fatty liver disease and fatty acid oxidation. (2006, background): “Hepatocyte death promotes the accelerated proliferation of surviving hepatocytes (9, 12, 23).”