Show simple item record

dc.contributor.authorMerlo, Aen
dc.contributor.authorBernardo-Castiñeira, Cen
dc.contributor.authorSáenz-de-Santa-María, Ien
dc.contributor.authorPitiot, ASen
dc.contributor.authorBalbín, Men
dc.contributor.authorAstudillo, Aen
dc.contributor.authorValdés, Nen
dc.contributor.authorScola, Ben
dc.contributor.authorDel Toro, Ren
dc.contributor.authorMendez-Ferrer, Simonen
dc.contributor.authorPiruat, JIen
dc.contributor.authorSuarez, Cen
dc.contributor.authorChiara, M-Den
dc.date.accessioned2017-08-16T12:43:01Z
dc.date.available2017-08-16T12:43:01Z
dc.date.issued2017-01-24en
dc.identifier.issn1949-2553
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/266509
dc.description.abstractThe hypoxia-inducible factor 1α (HIF-1α) and its microRNA target, miR-210, are candidate tumor-drivers of metabolic reprogramming in cancer. Neuroendocrine neoplasms such as paragangliomas (PGLs) are particularly appealing for understanding the cancer metabolic adjustments because of their associations with deregulations of metabolic enzymes, such as succinate dehydrogenase (SDH), and the von Hippel Lindau (VHL) gene involved in HIF-1α stabilization. However, the role of miR-210 in the pathogenesis of SDH-related tumors remains an unmet challenge. Herein is described an in vivo genetic analysis of the role of VHL, HIF1A and SDH on miR-210 by using knockout murine models, siRNA gene silencing, and analyses of human tumors. HIF-1α knockout abolished hypoxia-induced miR-210 expression in vivo but did not alter its constitutive expression in paraganglia. Normoxic miR-210 levels substantially increased by complete, but not partial, VHL silencing in paraganglia of knockout VHL-mice and by over-expression of p76del-mutated pVHL. Similarly, VHL-mutated PGLs, not those with decreased VHL-gene/mRNA dosage, over-expressed miR-210 and accumulate HIF-1α in most tumor cells. Ablation of SDH activity in SDHD-null cell lines or reduction of the SDHD or SDHB protein levels elicited by siRNA-induced gene silencing did not induce miR-210 whereas the presence of SDH mutations in PGLs and tumor-derived cell lines was associated with mild increase of miR-210 and the presence of a heterogeneous, HIF-1α-positive and HIF-1α-negative, tumor cell population. Thus, activation of HIF-1α is likely an early event in VHL-defective PGLs directly linked to VHL mutations, but it is a late event favored but not directly triggered by SDHx mutations. This combined analysis provides insights into the mechanisms of HIF-1α/miR-210 regulation in normal and tumor tissues potentially useful for understanding the pathogenesis of cancer and other diseases sharing similar underpinnings.
dc.languageengen
dc.language.isoenen
dc.subjecthypoxia inducible factoren
dc.subjectmiR-210en
dc.subjectparagangliomasen
dc.subjectsuccinate dehydrogenaseen
dc.subjectvon hippel lindauen
dc.titleRole of VHL, HIF1A and SDH on the expression of miR-210: Implications for tumoral pseudo-hypoxic fate.en
dc.typeArticle
prism.endingPage6717
prism.issueIdentifier4en
prism.publicationDate2017en
prism.publicationNameOncotargeten
prism.startingPage6700
prism.volume8en
dc.identifier.doi10.17863/CAM.10742
dcterms.dateAccepted2016-12-13en
rioxxterms.versionofrecord10.18632/oncotarget.14265en
rioxxterms.versionVoRen
rioxxterms.licenseref.urihttp://www.rioxx.net/licenses/all-rights-reserveden
rioxxterms.licenseref.startdate2017-01-24en
dc.contributor.orcidMendez-Ferrer, Simon [0000-0002-9805-9988]
dc.identifier.eissn1949-2553
rioxxterms.typeJournal Article/Reviewen
pubs.funder-project-idMRC (MC_PC_12009)
pubs.funder-project-idECH2020 EUROPEAN RESEARCH COUNCIL (ERC) (648765)


Files in this item

Thumbnail

This item appears in the following Collection(s)

Show simple item record