Article (Scientific journals)
Hypoxia-responsive miR-210 promotes self-renewal capacity of colon tumor-initiating cells by repressing ISCU and by inducing lactate production
ULLMANN, Pit; qureshi-baig, komal; RODRIGUEZ, Fabien et al.
2016In Oncotarget, 7 (40), p. 97-114
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Keywords :
colorectal cancer; tumor-initiating cell; hypoxia; miR-210; self-renewal capacity
Abstract :
[en] 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.
Disciplines :
Biochemistry, biophysics & molecular biology
Author, co-author :
ULLMANN, Pit ;  University of Luxembourg > Faculty of Science, Technology and Communication (FSTC) > Life Science Research Unit
qureshi-baig, komal
RODRIGUEZ, Fabien ;  University of Luxembourg > Faculty of Science, Technology and Communication (FSTC) > Life Science Research Unit
GINOLHAC, Aurélien  ;  University of Luxembourg > Faculty of Science, Technology and Communication (FSTC) > Life Science Research Unit
nonnenmacher, yannic;  University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB)
TERNES, Dominik ;  University of Luxembourg > Faculty of Science, Technology and Communication (FSTC) > Life Science Research Unit
Weiler, Jil
Gaebler, Karoline
bahlawane, Christelle
hiller, karsten
HAAN, Serge ;  University of Luxembourg > Faculty of Science, Technology and Communication (FSTC) > Life Science Research Unit
LETELLIER, Elisabeth ;  University of Luxembourg > Faculty of Science, Technology and Communication (FSTC) > Life Science Research Unit
External co-authors :
no
Language :
English
Title :
Hypoxia-responsive miR-210 promotes self-renewal capacity of colon tumor-initiating cells by repressing ISCU and by inducing lactate production
Publication date :
04 October 2016
Journal title :
Oncotarget
eISSN :
1949-2553
Publisher :
Impact Journals, Albany, United States - New York
Volume :
7
Issue :
40
Pages :
97-114
Peer reviewed :
Peer Reviewed verified by ORBi
Focus Area :
Systems Biomedicine
FnR Project :
FNR3093113 - Influence Of Hypoxia On The Metabolome Of Colon Cancer Stem Cells., 2011 (01/01/2012-30/11/2015) - Komal Baig
Funders :
Fondation Cancer
the Fondation du Pélican de Mie
Available on ORBilu :
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