2026-06-14T03:38:03Zhttps://repisalud.isciii.es/rest/oai/request

oai:repisalud.isciii.es:20.500.12105/51662024-09-27T09:18:09Zcom_20.500.12105_19604com_20.500.12105_2051col_20.500.12105_19605

00925njm 22002777a 4500 dc Merlo, Anna author Bernardo-Castineira, Cristobal author Sáenz-de-Santa-María, Inés author Pitiot, Ana S. author Balbin, Milagros author Astudillo, Aurora author Valdes, Nuria author Scola, Bartolome author Del Toro, Raquel author Mendez-Ferrer, Simon author Piruat, Jose I. author Suarez, Carlos author Chiara, Maria-Dolores author 2017 The hypoxia-inducible factor 1 alpha (HIF-1 alpha) 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-1 alpha 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-1 alpha 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-1 alpha 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-1 alpha-positive and HIF-1 alpha-negative, tumor cell population. Thus, activation of HIF-1 alpha 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-1 alpha/miR-210 regulation in normal and tumor tissues potentially useful for understanding the pathogenesis of cancer and other diseases sharing similar underpinnings. Oncotarget. 2017; 8(4):6700-17 10.18632/oncotarget.14265 1949-2553 Oncotarget 28036268 http://hdl.handle.net/20.500.12105/5166 Succinate dehydrogenase Hypoxia inducible factor Von hippel lindau Paragangliomas miR-210 HIPPEL-LINDAU-DISEASE RENAL-CELL CARCINOMA SUPPRESSOR PROTEIN NECK PARAGANGLIOMAS SIGNALING PATHWAY INDUCIBLE FACTORS GENE-MUTATIONS TCA CYCLE IN-VITRO PHEOCHROMOCYTOMAS Role of VHL, HIF1A and SDH on the expression of miR-210: Implications for tumoral pseudo-hypoxic fate