title: Hypoxia modulates HLA-G gene expression in tumor cells.
abstract: Human leukocyte antigen G (HLA-G) molecules are expressed in cytotrophoblasts and play a key role in maintaining immune tolerance at the maternal-fetal interface. HLA-G expression was also reported in inflammatory diseases, organ transplantation, and malignant tumors. The regulatory mechanisms of HLA-G gene expression differ from those of classical HLA class I genes and are still only partially elucidated. Focusing on tumor cells, we previously demonstrated a tight control of HLA-G gene expression by cis-acting epigenetic mechanisms. In the present study, we hypothesized that these processes are dependent of microenvironment conditions, and more particularly, stress conditions like hypoxia. Cellular response to hypoxia is mainly driven by a key transcription factor, hypoxia-inducible factor 1 (HIF-1), and other factors, such as NF-kappaB, involved in angiogenesis and cell survival. Here we confirmed the influence of hypoxia on HLA-G gene induction in the HLA-G-negative M8 melanoma cell line. Moreover, upon treatment with the hypoxia-mimicking desferrioxamine, we demonstrated a decrease in HLA-G gene expression in melanoma FON and choriocarcinoma JEG-3 cell lines, both expressing constitutively HLA-G. Finally, we demonstrated for the first time that the modulation of HLA-G gene expression is dependent of HIF-1 stabilization and thus might be relevant for the control of HLA-G gene expression in hypoxic tumors.
authors.affiliation: Commissariat à l'Energie Atomique, Service de Recherches en Hémato-Immunologie, Direction des Sciences du Vivant/Dèpartement de Recherche Médicale, Hôpital Saint-Louis, Institut Universitaire d'Hématologie, Paris, France.
authors.forename: Gaël
authors.initials: G
authors.lastname: Mouillot
authors.forename: Céline
authors.initials: C
authors.lastname: Marcou
authors.forename: Inès
authors.initials: I
authors.lastname: Zidi
authors.forename: Christine
authors.initials: C
authors.lastname: Guillard
authors.forename: Déborah
authors.initials: D
authors.lastname: Sangrouber
authors.forename: Edgardo D
authors.initials: ED
authors.lastname: Carosella
authors.forename: Philippe
authors.initials: P
authors.lastname: Moreau
mesh_terms: D045744:Cell Line, Tumor; D002822:Choriocarcinoma / Q000276:immunology* / Q000378:metabolism; D006680:HLA Antigens / Q000096:biosynthesis / Q000235:genetics*; D059951:HLA-G Antigens; D015395:Histocompatibility Antigens Class I / Q000096:biosynthesis / Q000235:genetics*; D006801:Humans; D000860:Hypoxia / Q000276:immunology* / Q000378:metabolism; D008545:Melanoma / Q000276:immunology* / Q000378:metabolism; D014158:Transcription, Genetic / Q000502:physiology
chemical_list: D006680:HLA Antigens; D059951:HLA-G Antigens; D015395:Histocompatibility Antigens Class I