Metabolomics,Unknown,Transcriptomics,Genomics,Proteomics

Dataset Information

IGR_HYPOXIA _MIR210_STUDY_SC

ABSTRACT: Hypoxia in the tumor microenvironment plays a crucial role in the evasion of immune surveillance by tumor cells. In this study, we aimed to identify the miRs regulated by hypoxia in NSCLC and melanoma and their putative involvement in the regulation of tumor susceptibility to antigen-specific cytotoxic T lymphocyte (CTL)-mediated killing. MicroRNA-210 (miR-210) was significantly induced in a hypoxia inducible factor 1 alpha (HIF-1_) dependent manner in NSCLC and melanoma cells. We show for the first time that miR-210 was expressed in hypoxic zones of human NSCLC tissues. Transfection of anti-miR-210 in both hypoxic NSCLC and melanoma cells resulted in a significant restoration of their susceptibility to autologous CTL-mediated lysis, independent of tumor cell recognition and CTL reactivity. A comprehensive approach using transcriptome analysis and argonaute protein immunoprecipitation indicated that PTPN, HOXA1and TP53I11 were regulated by miR-210 in hypoxic IGR-Heu cells. Simultaneous silencing of PTPN, HOXA1 and TP53I11 resulted in a dramatic decrease in target susceptibility to CTL-mediated lysis. This is the first report showing that hypoxia-induced miR-210 regulates tumor cell susceptibility to CTL-mediated lysis in part by suppressing PTPN, HOXA1 and TP53I11 expression. These studies suggest that miR-210 plays a potential role in the regulation of anti-tumor immune responses. The experience consists in 16 hybridizations on human miRNA Agilent arrays in one color, with 2 types of cell lines (HeuN and Na8) and 3 time of hypoxy induction (1% O2) (6, 16 and 24 hours) in comparison with normoxy (21% O2) at t=0. The hybridizations are made in replicates.

ORGANISM(S): Homo sapiens

SUBMITTER: Philippe DESSEN

PROVIDER: E-MTAB-1157 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Publications

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

Noman Muhammad Zaeem MZ Buart Stéphanie S Romero Pedro P Ketari Sami S Janji Bassam B Mari Bernard B Mami-Chouaib Fathia F Chouaib Salem S

Cancer research 20120907 18

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 ...[more]

PMID: 22962263

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Project description:The resistance of hypoxic cells to radiotherapy and chemotherapy is a major problem in the treatment of cancer. Recently, an additional level of Hypoxia Inducible Factor (HIF) dependent transcriptional regulation has emerged involving modulation of a specific set of miRNAs including miR-210. We have recently shown that HIF-1 induction of miR-210 also stabilizes HIF-1 through a positive regulatory loop. We therefore hypothesized that by stabilizing HIF-1 in normoxia, miR-210 may protect cancer cells from radiation. We developed Non-Small Cell Lung Cancer (NSCLC)-derived cell lines (A549 and H1975) stably expressing miR-210 (pmiR-210) or a control miRNA (pmiR-Ctl). MiR-210 expressing cells showed a significant stabilization of HIF-1 associated with mitochondrial defects and a glycolytic phenotype. The cells were subjected to radiation levels ranging from 0 to 10Gy in normoxia and hypoxia. Cells expressing miR-210 in normoxia had the same level of resistance than control cells in hypoxia. pmiR-210 cells under hypoxia showed a low mortality rate due to a decrease in apoptosis and an ability to grow even at 10Gy. We have established that radioresistance was independent of p53 and cell cycle status. In addition, we show here that genomic double strand breaks (DSB) foci disappeared faster in pmiR-210 than in pmiR-Ctl cells, suggesting that miR-210 expression promotes a more efficient DSB repair. Finally, HIF-1 invalidation in pmiR-210 cells (pmiR-210/HIF-1-) abolished radioresistance of cells showing that this mechanism was dependent upon HIF-1. In conclusion, miR-210 appears to be a major component in the radioresistance of hypoxic cancer cells. Given the high stability of most miRNAs, this advantage could even be used by tumor cells in conditions where hypoxia may not be present anymore and strongly suggests that strategies targeting miR-210 would enhance tumor radiosensitization. To identify the set of transcripts targeted by miR-210, we overexpressed has-miR-210 or a control miRNA (ce-miR-67) in human lung adenocarcinoma A549 cells by transduction using lentivirus. The resulting pmiR-67 and pmiR-210 that stably overexpress miR-210 were selected by puromycin. RNA samples were harvested at 2 different times following cell plating (24 hours or 48 hours). Experiments were performed in dye-swap.

Dataset Information

IGR_HYPOXIA _MIR210_STUDY_SC

Publications

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

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