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

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