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Article Dans Une Revue Cell Death and Differentiation Année : 2010

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

Thomas Bertero
Paul Hofman
Pascal Barbry

Résumé

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. 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, a subunit of Succinate Dehydrogenase (SDH) was validated as a bona fide miR-210 target, SDHD knockdown mimicking 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 components genes with important consequences on cell metabolism, survival and modulation of HIF-1 activity. These observations help explain contradictory data about miR-210 expression and its putative function in solid tumors.
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hal-00581855 , version 1 (01-04-2011)

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Bernard Mari, Marie-Pierre Puissegur, Nathalie Mazure, Thomas Bertero, Ludivine Pradelli, et al.. miR-210 is overexpressed in late stages of lung cancer and mediates mitochondrial alterations associated with modulation of HIF-1 activity. Cell Death and Differentiation, 2010, ⟨10.1038/cdd.2010.119⟩. ⟨hal-00581855⟩

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