Abstract
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.
Highlights
A defining hallmark of cancer is metabolic reprograming
Ablation of succinate dehydrogenase (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, hypoxia-inducible factor 1a (HIF-1a)-positive and hypoxia-inducible factors (HIF)-1a-negative, tumor cell population
We first addressed whether the expression of miR210 in the paraganglionic system is regulated by von Hippel Lindau (VHL) and/or HIF-1α activity in vivo
Summary
A defining hallmark of cancer is metabolic reprograming. Most of cancer cells use glycolysis-based metabolism for proliferation and reprogramming of the tricarboxylic acid cycle and mitochondrial oxidative phosphorylation to adapt to challenging conditions [1]. Aside this general cancer feature, there is a wealth of evidences proving that altered metabolic enzymes and their metabolites are oncogenic and not a product of tumor proliferation [2] This is relevant in pheochromocytomas and paragangliomas (PCC/PGLs) which frequently develop in patients with germline mutations of genes encoding the succinate dehydrogenase mitochondrial complex II (SDH). These associations provide a useful tumor model to unravel the molecular connections between mitochondrial activity and cancer. VHL-PGLs, in addition to accumulate HIF-1α, express low levels of SDHB likely as a result of miR-210 upregulation which represses expression of other genes essential for mitochondrial metabolism [17]. These premises encouraged us to carry out an in-depth analysis of the role of HIF-1α, SDH, and VHL on miR-210 expression by using knockout murine models and analyses of human tumor material
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
