title: Hypoxia-responsive miR-210 promotes self-renewal capacity of colon tumor-initiating cells by repressing ISCU and by inducing lactate production.
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.
authors: Life Sciences Research Unit, University of Luxembourg, L-4367 Belvaux, Luxembourg.
authors: Pit
authors: P
authors: Ullmann
authors: Life Sciences Research Unit, University of Luxembourg, L-4367 Belvaux, Luxembourg.
authors: Komal
authors: K
authors: Qureshi-Baig
authors: Life Sciences Research Unit, University of Luxembourg, L-4367 Belvaux, Luxembourg.
authors: Fabien
authors: F
authors: Rodriguez
authors: Life Sciences Research Unit, University of Luxembourg, L-4367 Belvaux, Luxembourg.
authors: Aurélien
authors: A
authors: Ginolhac
authors: Luxembourg Centre for Systems Biomedicine, L-4367 Belvaux, Luxembourg.
authors: Yannic
authors: Y
authors: Nonnenmacher
authors: Life Sciences Research Unit, University of Luxembourg, L-4367 Belvaux, Luxembourg.
authors: Dominik
authors: D
authors: Ternes
authors: Life Sciences Research Unit, University of Luxembourg, L-4367 Belvaux, Luxembourg.
authors: Jil
authors: J
authors: Weiler
authors: Life Sciences Research Unit, University of Luxembourg, L-4367 Belvaux, Luxembourg.
authors: Karoline
authors: K
authors: Gäbler
authors: Life Sciences Research Unit, University of Luxembourg, L-4367 Belvaux, Luxembourg.
authors: Christelle
authors: C
authors: Bahlawane
authors: Luxembourg Centre for Systems Biomedicine, L-4367 Belvaux, Luxembourg.
authors: Karsten
authors: K
authors: Hiller
authors: Life Sciences Research Unit, University of Luxembourg, L-4367 Belvaux, Luxembourg.
authors: Serge
authors: S
authors: Haan
authors: Life Sciences Research Unit, University of Luxembourg, L-4367 Belvaux, Luxembourg.
authors: Elisabeth
authors: E
authors: Letellier
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D063646:Carcinogenesis; D000066673:Cell Self Renewal; D003106:Colon / Q000473:pathology*; D003110:Colonic Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D000860:Hypoxia / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D007506:Iron-Sulfur Proteins / Q000235:genetics / Q000378:metabolism*; D019344:Lactic Acid / Q000378:metabolism; D008297:Male; D035683:MicroRNAs / Q000235:genetics*; D008875:Middle Aged; D009367:Neoplasm Staging; D014411:Neoplastic Stem Cells / Q000502:physiology*; D034741:RNA, Small Interfering / Q000235:genetics; D014407:Tumor Cells, Cultured
chemical_list: C506160:ISCU protein, human; D007506:Iron-Sulfur Proteins; C543800:MIRN210 microRNA, human; D035683:MicroRNAs; D034741:RNA, Small Interfering; D019344:Lactic Acid
keywords: colorectal cancer; hypoxia; miR-210; self-renewal capacity; tumor-initiating cell