A new HIF‐1α/RANTES‐driven pathway to hepatocellular carcinoma mediated by germline haploinsufficiency of SART1/HAF in mice
| Autor: | Robert Lemos, Garth Powis, Lewis R. Roberts, Carl F. Ware, Xiuping Liu, John R. Sedy, Vasileos Bekiaris, Timothy Sargis, Adriana Charbono, Mei Yee Koh, Geoffrey Grandjean, Mihai Gagea, Galina Kiriakova |
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| Rok vydání: | 2016 |
| Předmět: |
Male
0301 basic medicine Chemokine medicine.medical_specialty Carcinoma Hepatocellular medicine.medical_treatment Haploinsufficiency Tumor initiation Article CCL5 Mice 03 medical and health sciences 0302 clinical medicine Immune system Fibrosis Internal medicine medicine Animals Humans Chemokine CCL5 Hepatology biology Fatty Acids Liver Neoplasms Fatty liver Hypoxia-Inducible Factor 1 alpha Subunit Ribonucleoproteins Small Nuclear medicine.disease Ubiquitin ligase Fatty Liver Mice Inbred C57BL 030104 developmental biology Endocrinology Cytokine Neutrophil Infiltration 030220 oncology & carcinogenesis Trans-Activators biology.protein Cancer research Female |
| Zdroj: | Hepatology. 63:1576-1591 |
| ISSN: | 1527-3350 0270-9139 |
| DOI: | 10.1002/hep.28468 |
| Popis: | 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 significantly different. Neutralization of circulating RANTES decreased liver neutrophilic infiltration and attenuated HCC tumor initiation/growth in SART1+/− mice. Conclusion: This work establishes a new tumor-suppressor role for HAF in immune cell function by preventing inappropriate HIF-1 activation in male mice and identifies RANTES as a novel therapeutic target for NASH and NASH-driven HCC. (Hepatology 2016;63:1576-1591) |
| Databáze: | OpenAIRE |
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