dc.creator | Merlo, Anna | es |
dc.creator | Bernardo Castiñeira, Cristobal | es |
dc.creator | Saenz de Santamaría, Inés | es |
dc.creator | Pitiot, Ana | es |
dc.creator | Balbín, Milagros | es |
dc.creator | Astudillo, Aurora | es |
dc.creator | Toro Estévez, Raquel del | es |
dc.creator | Chiara, María D. | es |
dc.date.accessioned | 2020-05-13T10:01:01Z | |
dc.date.available | 2020-05-13T10:01:01Z | |
dc.date.issued | 2016 | |
dc.identifier.citation | Merlo, A., Bernardo Castiñeira, C., Saenz de Santamaría, I., Pitiot, A., Balbín, M., Astudillo, A.,...,Chiara, M.D. (2016). Role of VHL, HIF1A and SDH on the expression of miR-210: Implications for tumoral pseudo-hypoxic fate. Oncotarget, 8 (4), 1-19. | |
dc.identifier.issn | 1945-2553 | es |
dc.identifier.uri | https://hdl.handle.net/11441/96542 | |
dc.description.abstract | The hypoxia-inducible factor 1a (HIF-1a) 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-1a 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, VHLmutated
PGLs, not those with decreased VHL-gene/mRNA dosage, over-expressed
miR-210 and accumulate HIF-1a 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-1a-positive and HIF-1a-negative,
tumor cell population. Thus, activation of HIF-1a is likely an early event in VHLdefective
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-1a/miR-210 regulation in normal and tumor tissues
potentially useful for understanding the pathogenesis of cancer and other diseases sharing similar underpinnings. | es |
dc.description.sponsorship | Instituto de Salud Carlos III FIS PI11/929 | es |
dc.description.sponsorship | Red Temática de Investigación Cooperativa en Cáncer RD12/0036/0015 Instituto de Salud Carlos III (ISCIII) | es |
dc.description.sponsorship | Ministerio de Economía y Competitividad y Fondo Europeo de Desarrollo Regional | es |
dc.description.sponsorship | Fondo Europeo de Desarrollo Regional (FEDER) (CIBERONC) | es |
dc.format | application/pdf | es |
dc.format.extent | 19 | es |
dc.language.iso | eng | es |
dc.publisher | Impact Journals | es |
dc.relation.ispartof | Oncotarget, 8 (4), 1-19. | |
dc.rights | Attribution-NonCommercial-NoDerivatives 4.0 Internacional | * |
dc.rights.uri | http://creativecommons.org/licenses/by-nc-nd/4.0/ | * |
dc.subject | Succinate dehydrogenase | es |
dc.subject | Von hippel lindau | es |
dc.subject | Hypoxia inducible factor | es |
dc.subject | Paragangliomas | es |
dc.subject | MiR-210 | es |
dc.title | Role of VHL, HIF1A and SDH on the expression of miR-210: Implications for tumoral pseudo-hypoxic fate | es |
dc.type | info:eu-repo/semantics/article | es |
dcterms.identifier | https://ror.org/03yxnpp24 | |
dc.type.version | info:eu-repo/semantics/publishedVersion | es |
dc.rights.accessRights | info:eu-repo/semantics/openAccess | es |
dc.contributor.affiliation | Universidad de Sevilla. Departamento de Fisiología Médica y Biofísica | es |
dc.identifier.doi | 10.18632/oncotarget14265 | es |
dc.journaltitle | Oncotarget | es |
dc.publication.volumen | 8 | es |
dc.publication.issue | 4 | es |
dc.publication.initialPage | 1 | es |
dc.publication.endPage | 19 | es |