Role of VHL, HIF1A and SDH on the expression of miR-210: Implications for tumoral pseudo-hypoxic fate
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Anna Merlo1,*, Cristóbal Bernardo-Castiñeira1,*, Inés Sáenz-de-Santa-María1, Ana S Pitiot2, Milagros Balbín2, Aurora Astudillo3, Nuria Valdés4, Bartolomé Scola5, Raquel Del Toro6,7, Simón Méndez-Ferrer6,8, José I Piruat7, Carlos Suarez1, María-Dolores Chiara1
1Otorhinolaryngology Service, Hospital Universitario Central de Asturias, Instituto Universitario de Oncología del Principado de Asturias, Universidad de Oviedo, CIBERONC, Oviedo, Spain
2Service of Molecular Oncology, Hospital Universitario Central de Asturias, Instituto Universitario de Oncología del Principado de Asturias, Universidad de Oviedo, Oviedo, Spain
3Service of Pathology, Hospital Universitario Central de Asturias, Instituto Universitario de Oncología del Principado de Asturias, Universidad de Oviedo, Oviedo, Spain
4Service of Endocrinology and Nutrition, Hospital Universitario Central de Asturias, Instituto Universitario de Oncología del Principado de Asturias, Universidad de Oviedo, Oviedo, Spain
5Otorhinolaryngology Service, Hospital Gregorio Marañón, Madrid, Spain
6Stem Cell Niche Pathophysiology Group, Centro Nacional de Investigaciones Cardiovasculares, Madrid, Spain
7Department of Cardiovascular Physiopahology, Instituto de Biomedicina de Sevilla (IBiS), Hospital Universitario Virgen del Rocío, CSIC, Universidad de Sevilla, Sevilla, Spain
8Stem Cell Institute and Department of Haematology, University of Cambridge and National Health Service Blood and Transplant, Cambridge Biomedical Campus, UK
*These authors have contributed equally to this work
María-Dolores Chiara, email: email@example.com
Keywords: succinate dehydrogenase, hypoxia inducible factor, von hippel lindau, paragangliomas, miR-210
Received: July 02, 2016 Accepted: December 13, 2016 Published: December 27, 2016
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.
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