title: miR-210 is overexpressed in late stages of lung cancer and mediates mitochondrial alterations associated with modulation of HIF-1 activity.
abstract: 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.
authors.affiliation: Institut de Pharmacologie Moléculaire et Cellulaire, CNRS UMR6097, Sophia Antipolis, France.
authors.forename: M-P
authors.initials: MP
authors.lastname: Puisségur
authors.forename: N M
authors.initials: NM
authors.lastname: Mazure
authors.forename: T
authors.initials: T
authors.lastname: Bertero
authors.forename: L
authors.initials: L
authors.lastname: Pradelli
authors.forename: S
authors.initials: S
authors.lastname: Grosso
authors.forename: K
authors.initials: K
authors.lastname: Robbe-Sermesant
authors.forename: T
authors.initials: T
authors.lastname: Maurin
authors.forename: K
authors.initials: K
authors.lastname: Lebrigand
authors.forename: B
authors.initials: B
authors.lastname: Cardinaud
authors.forename: V
authors.initials: V
authors.lastname: Hofman
authors.forename: S
authors.initials: S
authors.lastname: Fourre
authors.forename: V
authors.initials: V
authors.lastname: Magnone
authors.forename: J E
authors.initials: JE
authors.lastname: Ricci
authors.forename: J
authors.initials: J
authors.lastname: Pouysségur
authors.forename: P
authors.initials: P
authors.lastname: Gounon
authors.forename: P
authors.initials: P
authors.lastname: Hofman
authors.forename: P
authors.initials: P
authors.lastname: Barbry
authors.forename: B
authors.initials: B
authors.lastname: Mari
mesh_terms: D017209:Apoptosis; D002289:Carcinoma, Non-Small-Cell Lung / Q000201:enzymology / Q000235:genetics* / Q000473:pathology / Q000648:ultrastructure; D053148:Caspase 3 / Q000378:metabolism; D053179:Caspase 7 / Q000378:metabolism; D015687:Cell Hypoxia / Q000235:genetics; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000235:genetics; D015536:Down-Regulation / Q000235:genetics; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D008175:Lung Neoplasms / Q000201:enzymology / Q000235:genetics* / Q000473:pathology / Q000648:ultrastructure; D035683:MicroRNAs / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D008928:Mitochondria / Q000201:enzymology / Q000473:pathology* / Q000648:ultrastructure; D024101:Mitochondrial Proteins / Q000378:metabolism; D009367:Neoplasm Staging; D010641:Phenotype; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism; D013385:Succinate Dehydrogenase / Q000378:metabolism; D015854:Up-Regulation / Q000235:genetics
chemical_list: C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; C543800:MIRN210 microRNA, human; D035683:MicroRNAs; D024101:Mitochondrial Proteins; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D013385:Succinate Dehydrogenase; D053148:Caspase 3; D053179:Caspase 7