Role of VHL, HIF1A and SDH on the expression of miR-210: implications for tumoral pseudo-hypoxic fate
| Autor: | Bartolomé Scola, Milagros Balbín, Aurora Astudillo, Anna Merlo, Raquel del Toro, Ana S. Pitiot, Nuria Valdés, José I. Piruat, Inés Sáenz-de-Santa-María, Simón Méndez-Ferrer, Cristóbal Bernardo-Castiñeira, Carlos Suárez, María-Dolores Chiara |
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| Přispěvatelé: | Instituto de Salud Carlos III, Ministerio de Economía y Competitividad (España), European Regional Development Fund (ERDF/FEDER), Instituto Universitario de Oncologia del Principado de Asturias, Red Temática de Investigación Cooperativa en Cáncer (España), European Commission, Obra Social Cajastur, Instituto Universitario de Oncología del Principado de Asturias, Mendez-Ferrer, Simon [0000-0002-9805-9988], Apollo - University of Cambridge Repository |
| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Oncology Male SDHB Metabolic reprogramming Gene mutation miR-210 Hypoxia inducible factor 0302 clinical medicine RENAL-CELL CARCINOMA Tumor Microenvironment Medicine PHEOCHROMOCYTOMAS Mice Knockout Protein Stability SUPPRESSOR PROTEIN 3. Good health TCA CYCLE Succinate dehydrogenase Gene Expression Regulation Neoplastic Phenotype Hypoxia-inducible factors Von Hippel-Lindau Tumor Suppressor Protein 030220 oncology & carcinogenesis INDUCIBLE FACTORS Female RNA Interference SIGNALING PATHWAY GENE-MUTATIONS Research Paper Signal Transduction Adult medicine.medical_specialty hypoxia inducible factor Paragangliomas Transfection HIPPEL-LINDAU-DISEASE Paraganglioma 03 medical and health sciences Internal medicine Cell Line Tumor Von hippel lindau Animals Humans Genetic Predisposition to Disease business.industry von hippel lindau Cancer IN-VITRO medicine.disease NECK PARAGANGLIOMAS succinate dehydrogenase Hypoxia-Inducible Factor 1 alpha Subunit paragangliomas Surgery MicroRNAs 030104 developmental biology HIF1A Mutation Tumor Hypoxia SDHD business Gene Deletion |
| Zdroj: | Scopus RUO. Repositorio Institucional de la Universidad de Oviedo instname Oncotarget RUO: Repositorio Institucional de la Universidad de Oviedo Universidad de Oviedo (UNIOVI) Digital.CSIC. Repositorio Institucional del CSIC Repisalud Instituto de Salud Carlos III (ISCIII) Repositorio Institucional de la Consejería de Sanidad de la Comunidad de Madrid Consejería de Sanidad de la Comunidad de Madrid |
| Popis: | The 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. This work was supported by Instituto de Salud Carlos III-Fondo de Investigación Sanitaria [FIS PI11/929]; Red Temática de Investigación Cooperativa en Cáncer [RD12/0036/0015] Instituto de Salud Carlos III (ISCIII), Spanish Ministry of Economy and Competitiveness & European Regional Development Fund (ERDF); the European Regional Development's funds (FEDER) (CIBERONC) and Obra Social CajAstur-Instituto Universitario de Oncología del Principado de Asturias. |
| Databáze: | OpenAIRE |
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