title: MiR-210 promotes a hypoxic phenotype and increases radioresistance in human lung cancer cell lines.
abstract: The resistance of hypoxic cells to radiotherapy and chemotherapy is a major problem in the treatment of cancer. Recently, an additional mode of hypoxia-inducible factor (HIF)-dependent transcriptional regulation, involving modulation of a specific set of micro RNAs (miRNAs), including miR-210, has emerged. We have recently shown that HIF-1 induction of miR-210 also stabilizes HIF-1 through a positive regulatory loop. Therefore, we hypothesized that by stabilizing HIF-1 in normoxia, miR-210 may protect cancer cells from radiation. We developed a non-small cell lung carcinoma (NSCLC)-derived cell line (A549) stably expressing miR-210 (pmiR-210) or a control miRNA (pmiR-Ctl). The miR-210-expressing cells showed a significant stabilization of HIF-1 associated with mitochondrial defects and a glycolytic phenotype. Cells were subjected to radiation levels ranging from 0 to 10 Gy in normoxia and hypoxia. Cells expressing miR-210 in normoxia had the same level of radioresistance as control cells in hypoxia. Under hypoxia, pmiR-210 cells showed a low mortality rate owing to a decrease in apoptosis, with an ability to grow even at 10 Gy. This miR-210 phenotype was reproduced in another NSCLC cell line (H1975) and in HeLa cells. We have established that radioresistance was independent of p53 and cell cycle status. In addition, we have shown that genomic double-strand breaks (DSBs) foci disappear 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 removed the radioresistant phenotype, showing that this mechanism is dependent on HIF-1. In conclusion, miR-210 appears to be a component of the radioresistance of hypoxic cancer cells. Given the high stability of most miRNAs, this advantage could be used by tumor cells in conditions where reoxygenation has occurred and suggests that strategies targeting miR-210 could enhance tumor radiosensitization.
authors.affiliation: Institut de Pharmacologie Moléculaire et Cellulaire (IPMC), Centre National de la Recherche Scientifique, CNRS UMR 7275, Sophia Antipolis, France.
authors.forename: S
authors.initials: S
authors.lastname: Grosso
authors.forename: J
authors.initials: J
authors.lastname: Doyen
authors.forename: S K
authors.initials: SK
authors.lastname: Parks
authors.forename: T
authors.initials: T
authors.lastname: Bertero
authors.forename: A
authors.initials: A
authors.lastname: Paye
authors.forename: B
authors.initials: B
authors.lastname: Cardinaud
authors.forename: P
authors.initials: P
authors.lastname: Gounon
authors.forename: S
authors.initials: S
authors.lastname: Lacas-Gervais
authors.forename: A
authors.initials: A
authors.lastname: Noël
authors.forename: J
authors.initials: J
authors.lastname: Pouysségur
authors.forename: P
authors.initials: P
authors.lastname: Barbry
authors.forename: N M
authors.initials: NM
authors.lastname: Mazure
authors.forename: B
authors.initials: B
authors.lastname: Mari
mesh_terms: D017209:Apoptosis / Q000528:radiation effects; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D015687:Cell Hypoxia / Q000235:genetics / Q000528:radiation effects; D045744:Cell Line, Tumor; D053903:DNA Breaks, Double-Stranded; D004260:DNA Repair; D005720:Gamma Rays; D015972:Gene Expression Regulation, Neoplastic / Q000528:radiation effects*; D006801:Humans; D000860:Hypoxia / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D051793:Hypoxia-Inducible Factor 1 / Q000235:genetics* / Q000378:metabolism; D008175:Lung Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism / Q000528:radiation effects; D011836:Radiation Tolerance; D015398:Signal Transduction / Q000528:radiation effects; D014158:Transcription, Genetic / Q000528:radiation effects
chemical_list: D051793:Hypoxia-Inducible Factor 1; C543800:MIRN210 microRNA, human; D035683:MicroRNAs