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

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 patientderived
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.