title: Hypoxia-inducible miR-210 regulates the susceptibility of tumor cells to lysis by cytotoxic T cells.
abstract: Hypoxia in the tumor microenvironment plays a central role in the evolution of immune escape mechanisms by tumor cells. In this study, we report the definition of miR-210 as a miRNA regulated by hypoxia in lung cancer and melanoma, documenting its involvement in blunting the susceptibility of tumor cells to lysis by antigen-specific cytotoxic T lymphocytes (CTL). miR-210 was induced in hypoxic zones of human tumor tissues. Its attenuation in hypoxic cells significantly restored susceptibility to autologous CTL-mediated lysis, independent of tumor cell recognition and CTL reactivity. A comprehensive approach using transcriptome analysis, argonaute protein immunoprecipitation, and luciferase reporter assay revealed that the genes PTPN1, HOXA1, and TP53I11 were miR-210 target genes regulated in hypoxic cells. In support of their primary importance in mediating the immunosuppressive effects of miR-210, coordinate silencing of PTPN1, HOXA1, and TP53I11 dramatically decreased tumor cell susceptibility to CTL-mediated lysis. Our findings show how miR-210 induction links hypoxia to immune escape from CTL-mediated lysis, by providing a mechanistic understanding of how this miRNA mediates immunosuppression in oxygen-deprived regions of tumors where cancer stem-like cells and metastatic cellular behaviors are known to evolve.
authors.affiliation: Unité INSERM U753, Institut de Cancérologie Gustave Roussy, 114 rue Edouard Vaillant, 94805 Villejuif, France.
authors.forename: Muhammad Zaeem
authors.initials: MZ
authors.lastname: Noman
authors.forename: Stéphanie
authors.initials: S
authors.lastname: Buart
authors.forename: Pedro
authors.initials: P
authors.lastname: Romero
authors.forename: Sami
authors.initials: S
authors.lastname: Ketari
authors.forename: Bassam
authors.initials: B
authors.lastname: Janji
authors.forename: Bernard
authors.initials: B
authors.lastname: Mari
authors.forename: Fathia
authors.initials: F
authors.lastname: Mami-Chouaib
authors.forename: Salem
authors.initials: S
authors.lastname: Chouaib
mesh_terms: D015153:Blotting, Western; D016923:Cell Death; D015687:Cell Hypoxia / Q000502:physiology; D045744:Cell Line, Tumor; D003602:Cytotoxicity, Immunologic / Q000276:immunology*; D005434:Flow Cytometry; D020868:Gene Silencing; D006801:Humans; D007150:Immunohistochemistry; D047468:Immunoprecipitation; D035683:MicroRNAs / Q000276:immunology* / Q000378:metabolism; D009369:Neoplasms / Q000276:immunology / Q000473:pathology; D034622:RNA Interference; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D014162:Transfection; D019139:Tumor Escape / Q000276:immunology*; D059016:Tumor Microenvironment / Q000502:physiology
chemical_list: C543800:MIRN210 microRNA, human; D035683:MicroRNAs