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

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

doi:10.18632/oncotarget.11772

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.

Highlights

Colorectal cancer (CRC) is among the most prevalent cancers worldwide with more than 1.3 million diagnoses and almost 700,000 deaths per year [1]
Low oxygen tension leads to an increased tumor-initiating cells (TICs) proportion in glioma patients [12, 15], drives gene expression of cancer cells towards a more immature phenotype [13], presses TIC-like cells derived from CRC cell lines into forming undifferentiated dense colonies [17], and induces reprogramming of nontumorigenic cells towards a TIC-like behavior [14, 16]
In the scope of this work, we show that hypoxia enhances the self-renewal capacity of both cell line- and patient-derived primary colon TIC cultures

Summary

Introduction

Colorectal cancer (CRC) is among the most prevalent cancers worldwide with more than 1.3 million diagnoses and almost 700,000 deaths per year [1]. A limited number of cells within CRC tissue as well as within conventional cancer cell lines displays TIC properties [4]. Studies on TIC biology have been limited so far, in part due to intense controversy regarding the use of surface markers for their isolation and characterization [5,6,7]. To address these issues, we have recently established and characterized different CRC spheroid cultures (SCs), both from patient samples and from conventional CRC cell lines, by rather relying on functional properties than on surface marker expression. We could show that these SCs retain most important characteristics of their tumor of origin and display pronounced TIC features, such as self-renewal capacity, tumorigenic potential, and chemoresistance [8]

Methods

Results

Conclusion