A new HIF-1α/RANTES-driven pathway to hepatocellular carcinoma mediated by germline haploinsufficiency of SART1/HAF in mice

Hepatology : Official Journal of the American Association for the Study of Liver Diseases
Mei Yee KohGarth Powis

Abstract

The hypoxia-inducible factor (HIF), HIF-1, is a central regulator of the response to low oxygen or inflammatory stress and plays an essential role in survival and function of immune cells. However, the mechanisms regulating nonhypoxic induction of HIF-1 remain unclear. Here, we assess the impact of germline heterozygosity of a novel, oxygen-independent ubiquitin ligase for HIF-1α: hypoxia-associated factor (HAF; encoded by SART1). SART1(-/-) mice were embryonic lethal, whereas male SART1(+/-) mice spontaneously recapitulated key features of nonalcoholic steatohepatitis (NASH)-driven hepatocellular carcinoma (HCC), including steatosis, fibrosis, and inflammatory cytokine production. Male, but not female, SART1(+/-) mice showed significant up-regulation of HIF-1α in circulating and liver-infiltrating immune cells, but not in hepatocytes, before development of malignancy. Additionally, Kupffer cells derived from male, but not female, SART1(+/-) mice produced increased levels of the HIF-1-dependent chemokine, regulated on activation, normal T-cell expressed and secreted (RANTES), compared to wild type. This was associated with increased liver-neutrophilic infiltration, whereas infiltration of lymphocytes and macrophages were not si...Continue Reading

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Citations

Jan 31, 2018·Nature Immunology·Marc RingelhanMathias Heikenwalder
Apr 18, 2018·Hepatology : Official Journal of the American Association for the Study of Liver Diseases·Francesca Romana PonzianiVincenzo Mazzaferro
Sep 11, 2019·Journal of Experimental & Clinical Cancer Research : CR·Yaojie FuHong Shen
Aug 5, 2020·The Journal of Clinical Investigation·Vincent Wai-Hin Yuen, Carmen Chak-Lui Wong
Apr 12, 2019·International Journal of Molecular Sciences·Antonio SircanaGiovanni Musso
Aug 25, 2020·Medicinal Chemistry Research : an International Journal for Rapid Communications on Design and Mechanisms of Action of Biologically Active Agents·Jian JinRussell A Prough
Aug 10, 2020·Experimental & Molecular Medicine·Seo-Young KooChang-Woo Lee
Nov 26, 2020·Cellular & Molecular Immunology·Benjamin RufTim F Greten
Mar 21, 2017·Experimental Cell Research·Julia GünterCarsten C Scholz
Jun 3, 2021·International Journal of Molecular Sciences·Kyoko OuraTsutomu Masaki

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