Hypoxia-inducible miR-210 regulates the susceptibility of tumor cells to lysis by cytotoxic T cells

Muhammad Zaeem Noman, Stéphanie Buart, Pedro Romero, Sami Ketari, Bassam Janji, Bernard Mari, Fathia Mami-Chouaib, Salem Chouaib*

*Corresponding author for this work

    Research output: Contribution to journalArticleResearchpeer-review

    144 Citations (Scopus)

    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.

    Original languageEnglish
    Pages (from-to)4629-4641
    Number of pages13
    JournalCancer Research
    Volume72
    Issue number18
    DOIs
    Publication statusPublished - 15 Sep 2012

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