Article (Scientific journals)
The microRNA-371~373 cluster represses colon cancer initiation and metastatic colonization by inhibiting the TGFBR2/ID1 signaling axis.
Ullmann, Pit; Rodriguez, Fabien; Schmitz, Martine et al.
2018In Cancer Research
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Abstract :
[en] The vast majority of colorectal cancer (CRC)-related deaths can be attributed to metastatic spreading of the disease. Therefore, deciphering molecular mechanisms of metastatic dissemination is a key prerequisite to improve future treatment options. With this aim, we took advantage of different CRC cell lines and recently established primary cultures enriched in colon cancer stem cells (CSCs) - also known as tumor-initiating cells (TICs) - to identify genes and microRNAs (miRNAs) with regulatory functions in CRC progression. We show here that metastasis-derived TICs display increased capacity for self-renewal, transforming growth factor beta (TGF-beta) signaling activity, and reduced expression of the miR-371~373 cluster compared to non-metastatic cultures. TGF-beta receptor 2 (TGFBR2) and aldehyde dehydrogenase A1 (ALDH1A1) were identified as important target genes of the miR-371~373 cluster. In addition, TGFBR2 repression, either by direct knockdown or indirectly via overexpression of the entire miR-371~373 cluster, decreased tumor-initiating potential of TICs. We observed significantly reduced in vitro self-renewal activity as well as lowered tumor-initiation and metastatic outgrowth capacity in vivo following stable overexpression of the miR-371~373 cluster in different colon TIC cultures. Inhibitor of DNA binding 1 (ID1) was affected by both TGFBR2 and miR-371~373 cluster alterations. Functional sphere and tumor formation as well as metastatic dissemination assays validated the link between miR-371~373 and ID1. Altogether, our results establish the miR-371~373/TGFBR2/ID1 signaling axis as a novel regulatory mechanism of TIC self-renewal and metastatic colonization.
Disciplines :
Biochemistry, biophysics & molecular biology
Author, co-author :
Ullmann, Pit ;  University of Luxembourg > Faculty of Science, Technology and Communication (FSTC) > Life Science Research Unit
Rodriguez, Fabien ;  University of Luxembourg > Faculty of Science, Technology and Communication (FSTC) > Life Science Research Unit
Schmitz, Martine ;  University of Luxembourg > Faculty of Science, Technology and Communication (FSTC) > Life Science Research Unit
Meurer, Steffen K.
Qureshi-Baig, Komal
Felten, Paul ;  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
Antunes, Laurent
Frasquilho, Sonia
Zugel, Nikolaus
Weiskirchen, Ralf
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
More authors (3 more) Less
External co-authors :
yes
Language :
English
Title :
The microRNA-371~373 cluster represses colon cancer initiation and metastatic colonization by inhibiting the TGFBR2/ID1 signaling axis.
Publication date :
2018
Journal title :
Cancer Research
ISSN :
1538-7445
Publisher :
American Association for Cancer Research, United States - Maryland
Peer reviewed :
Peer Reviewed verified by ORBi
Focus Area :
Systems Biomedicine
Commentary :
Copyright (c)2018, American Association for Cancer Research.
Available on ORBilu :
since 24 November 2018

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