title: A new HIF-1α/RANTES-driven pathway to hepatocellular carcinoma mediated by germline haploinsufficiency of SART1/HAF in mice.
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 significantly different. Neutralization of circulating RANTES decreased liver neutrophilic infiltration and attenuated HCC tumor initiation/growth in SART1(+/-) mice.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA.
authors.forename: Mei Yee
authors.initials: MY
authors.lastname: Koh
authors.affiliation: The University of Texas M.D. Anderson Cancer Center, Houston, TX.
authors.forename: Mihai
authors.initials: M
authors.lastname: Gagea
authors.affiliation: Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA.
authors.forename: Timothy
authors.initials: T
authors.lastname: Sargis
authors.affiliation: Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA.
authors.forename: Robert
authors.initials: R
authors.lastname: Lemos
authors.affiliation: Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA.
authors.forename: Geoffrey
authors.initials: G
authors.lastname: Grandjean
authors.affiliation: Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA.
authors.forename: Adriana
authors.initials: A
authors.lastname: Charbono
authors.affiliation: Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA.
authors.forename: Vasileos
authors.initials: V
authors.lastname: Bekiaris
authors.affiliation: Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA.
authors.forename: John
authors.initials: J
authors.lastname: Sedy
authors.affiliation: The University of Texas M.D. Anderson Cancer Center, Houston, TX.
authors.forename: Galina
authors.initials: G
authors.lastname: Kiriakova
authors.affiliation: The University of Texas M.D. Anderson Cancer Center, Houston, TX.
authors.forename: Xiuping
authors.initials: X
authors.lastname: Liu
authors.affiliation: Mayo Clinic, Rochester, MN.
authors.forename: Lewis R
authors.initials: LR
authors.lastname: Roberts
authors.affiliation: Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA.
authors.forename: Carl
authors.initials: C
authors.lastname: Ware
authors.affiliation: Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA.
authors.forename: Garth
authors.initials: G
authors.lastname: Powis
mesh_terms: D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000209:etiology*; D018946:Chemokine CCL5 / Q000502:physiology*; D005227:Fatty Acids / Q000378:metabolism; D005234:Fatty Liver / Q000209:etiology; D005260:Female; D057895:Haploinsufficiency; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000502:physiology*; D008113:Liver Neoplasms / Q000209:etiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D020556:Neutrophil Infiltration; D017411:Ribonucleoproteins, Small Nuclear; D015534:Trans-Activators / Q000235:genetics*
chemical_list: C503460:Ccl5 protein, mouse; D018946:Chemokine CCL5; D005227:Fatty Acids; C497443:Hif1a protein, mouse; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D017411:Ribonucleoproteins, Small Nuclear; C411898:Sart1 protein, mouse; D015534:Trans-Activators