Hypoxia-responsive miR-210 promotes self-renewal capacity of colon tumor-initiating cells by repressing ISCU and by inducing lactate production

摘要: // Pit Ullmann 1 , Komal Qureshi-Baig Fabien Rodriguez Aurelien Ginolhac Yannic Nonnenmacher 2 Dominik Ternes Jil Weiler Karoline Gabler Christelle Bahlawane Karsten Hiller Serge Haan Elisabeth Letellier Life Sciences Research Unit, University of Luxembourg, L-4367 Belvaux, Luxembourg Centre for Systems Biomedicine, Correspondence to: Letellier, email: elisabeth.letellier@uni.lu Keywords: colorectal cancer, tumor-initiating cell, hypoxia, miR-210, self-renewal capacity Received: May 20, 2016      Accepted: August 25, Published: 31, 2016 ABSTRACT Low oxygen concentrations (hypoxia) are known to affect the cellular metabolism and have been suggested regulate a subpopulation cancer cells with tumorigenic properties, so-called (TICs). To better understand mechanism hypoxia-induced TIC activation, we set out study role hypoxia-responsive miRNAs in recently established colon patient-derived TICs. We were able show that low consistently lead upregulation miR-210 different primary TIC-enriched cultures. Both stable overexpression knockdown its target gene ISCU resulted enhanced self-renewal. could validate properties miR- 210 vivo experiments by showing ectopic expression results increased tumor incidence. Furthermore, correlated reduced TCA cycle activity lactate levels. Importantly, blocking production via inhibition LDHA, reverse promoting effect on capacity, thereby emphasizing regulatory impact glycolytic phenotype properties. Finally, assessing levels patient tissue, demonstrate clinical relevance miR-210/ISCU signaling axis carcinoma. Taken together, our highlights importance regulation initiation.