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miR-210 is overexpressed in late stages of lung cancer and mediates mitochondrial alterations associated with modulation of HIF-1 activity

2010; Springer Nature; Volume: 18; Issue: 3 Linguagem: Inglês

10.1038/cdd.2010.119

1476-5403

Marie-Pierre Puisségur, Nathalie M. Mazure, Thomas Bertero, Ludivine A. Pradelli, Sébastien Grosso, Karine Robbe-Sermesant, Thomas Maurin, Kévin Lebrigand, Bruno Cardinaud, Véronique Hofman, Sandra Fourré, Virginie Magnone, Jean‐Ehrland Ricci, Jacques Pouysségur, Pierre Gounon, Paul Hofman, Pascal Barbry, Bernard Mari,

RNA modifications and cancer

Following the identification of a set of hypoxia-regulated microRNAs (miRNAs), recent studies have highlighted the importance of miR-210 and of its transcriptional regulation by the transcription factor hypoxia-inducible factor-1 (HIF-1). We report here that miR-210 is overexpressed at late stages of non-small cell lung cancer. Expression of miR-210 in lung adenocarcinoma A549 cells caused an alteration of cell viability associated with induction of caspase-3/7 activity. miR-210 induced a loss of mitochondrial membrane potential and the apparition of an aberrant mitochondrial phenotype. The expression profiling of cells overexpressing miR-210 revealed a specific signature characterized by enrichment for transcripts related to 'cell death' and 'mitochondrial dysfunction', including several subunits of the electron transport chain (ETC) complexes I and II. The transcript coding for one of these ETC components, SDHD, subunit D of succinate dehydrogenase complex (SDH), was validated as a bona fide miR-210 target. Moreover, SDHD knockdown mimicked miR-210-mediated mitochondrial alterations. Finally, miR-210-dependent targeting of SDHD was able to activate HIF-1, in line with previous studies linking loss-of-function SDH mutations to HIF-1 activation. miR-210 can thus regulate mitochondrial function by targeting key ETC component genes with important consequences on cell metabolism, survival and modulation of HIF-1 activity. These observations help explain contradictory data regarding miR-210 expression and its putative function in solid tumors.