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

Pit Ullmann, Komal Qureshi-Baig, Fabien Rodriguez, Aurélien Ginolhac, Yannic Nonnenmacher, Dominik Ternes, Jil Weiler, Karoline Gäbler, Christelle Bahlawane, Karsten Hiller, Serge Haan, Elisabeth Letellier*

*Corresponding author for this work

Research output: Contribution to journalArticleResearchpeer-review

39 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)65454-65470
Number of pages17
JournalOncotarget
Volume7
Issue number40
DOIs
Publication statusPublished - 2016
Externally publishedYes

Keywords

  • Colorectal cancer
  • Hypoxia
  • MiR-210
  • Self-renewal capacity
  • Tumor-initiating cell

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