title: Hypoxia-dependent inhibition of tumor cell susceptibility to CTL-mediated lysis involves NANOG induction in target cells.
abstract: Hypoxia is a major feature of the solid tumor microenvironment and is known to be associated with tumor progression and poor clinical outcome. Recently, we reported that hypoxia protects human non-small cell lung tumor cells from specific lysis by stabilizing hypoxia-inducible factor-1α and inducing STAT3 phosphorylation. In this study, we show that NANOG, a transcription factor associated with stem cell self renewal, is a new mediator of hypoxia-induced resistance to specific lysis. Our data indicate that under hypoxic conditions, NANOG is induced at both transcriptional and translational levels. Knockdown of the NANOG gene in hypoxic tumor cells is able to significantly attenuate hypoxia-induced tumor resistance to CTL-dependent killing. Such knockdown correlates with an increase of target cell death and an inhibition of hypoxia-induced delay of DNA replication in these cells. Interestingly, NANOG depletion results in inhibition of STAT3 phosphorylation and nuclear translocation. To our knowledge, this study is the first to show that hypoxia-induced NANOG plays a critical role in tumor cell response to hypoxia and promotes tumor cell resistance to Ag-specific lysis.
authors.affiliation: Institut Gustave Roussy, INSERM Unité 753, 94800 Villejuif, France.
authors.forename: Meriem
authors.initials: M
authors.lastname: Hasmim
authors.forename: Muhammad Zaeem
authors.initials: MZ
authors.lastname: Noman
authors.forename: Jessica
authors.initials: J
authors.lastname: Lauriol
authors.forename: Houssem
authors.initials: H
authors.lastname: Benlalam
authors.forename: Aude
authors.initials: A
authors.lastname: Mallavialle
authors.forename: Filippo
authors.initials: F
authors.lastname: Rosselli
authors.forename: Fathia
authors.initials: F
authors.lastname: Mami-Chouaib
authors.forename: Catherine
authors.initials: C
authors.lastname: Alcaide-Loridan
authors.forename: Salem
authors.initials: S
authors.lastname: Chouaib
mesh_terms: D015153:Blotting, Western; D015687:Cell Hypoxia / Q000235:genetics / Q000276:immunology*; D045744:Cell Line, Tumor; D002469:Cell Separation; D005434:Flow Cytometry; D015870:Gene Expression; D005786:Gene Expression Regulation / Q000276:immunology; D018398:Homeodomain Proteins / Q000096:biosynthesis* / Q000235:genetics / Q000276:immunology; D006801:Humans; D018613:Microscopy, Confocal; D000071317:Nanog Homeobox Protein; D009369:Neoplasms / Q000276:immunology* / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology* / Q000378:metabolism; D059016:Tumor Microenvironment / Q000235:genetics / Q000276:immunology
chemical_list: D018398:Homeodomain Proteins; C486780:NANOG protein, human; D000071317:Nanog Homeobox Protein