TY - JOUR
T1 - Tumor suppressor miR-215 counteracts hypoxia-induced colon cancer stem cell activity
AU - Ullmann, Pit
AU - Nurmik, Martin
AU - Schmitz, Martine
AU - Rodriguez, Fabien
AU - Weiler, Jil
AU - Qureshi-Baig, Komal
AU - Felten, Paul
AU - Nazarov, Petr V.
AU - Nicot, Nathalie
AU - Zuegel, Nikolaus
AU - Haan, Serge
AU - Letellier, Elisabeth
N1 - Funding Information:
The authors would like to thank all the contributing surgeons and nurses from the Centre Hospitalier Emile Mayrisch, the Centre Hospitalier du Luxembourg, and the Clinical and Epidemiological Investigation Centre of the Luxembourg Institute of Health (LIH) for their work with the patients. We would also like to thank our collaborators from the Laboratoire National de Santé (LNS), particularly Michel Mittelbronn and Daniel Val Garijo, as well as from the Integrated Biobank of Luxembourg (IBBL), particularly Fay Betsou and Nikolai Goncharenko, for pathology services, the overall set-up of the patient sample collection, and RNA extraction. We are also grateful to Djalil Coowar and Marthe Schmit for managing the animal facility of the University of Luxembourg and to Aurélien Ginolhac for substantial bioinformatics support. We are grateful to all the current and former members of the Genomics Research Unit of the LIH, for performing the microarray experiments and for providing additional bioinformatics support. We would also like to thank Karoline Gäbler, Alexandra Ulla, Dominik Ternes, and Christelle Bahlawane from the LSRU/IBBL for additional help with data analysis, establishment of in vitro assays, and critical discussions. This project was supported by the Fondation Cancer (E. Letellier and S. Haan received grant F1R-LSC-PAU-13HY2C ) and by the Fonds National de la Recherche (FNR) Luxembourg (K. Qureshi-Baig received grant AFR/3093113 , P. Ullmann received grant AFR/7855578 , and E. Letellier received grants C16/BM/11282028 and PoC18/12554295 ). K. Qureshi-Baig and P. Ullmann were also supported by the Fondation du Pélican de Mie and Pierre Hippert-Faber under the aegis of the Fondation de Luxembourg . The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Publisher Copyright:
© 2019 The Author(s)
PY - 2019/5/28
Y1 - 2019/5/28
N2 - Cancer stem cells, also known as tumor-initiating cells (TICs), are a population of aggressive and self-renewing cells that are responsible for the initiation and progression of many cancers, including colorectal carcinoma. Intratumoral hypoxia, i.e. reduced oxygen supply following uncontrolled proliferation of cancer cells, is thought to support TIC activity by inducing specific hypoxia-responsive mechanisms that are not yet entirely understood. Using previously established and fully characterized patient-derived TIC cultures, we could observe increased sphere and colony formation under hypoxic conditions. Mechanistically, microRNA (miRNA)-profiling experiments allowed us to identify miR-215 as one of the main hypoxia-induced miRNAs in primary colon TICs. Through stable overexpression of miR-215, followed by a set of functional in vitro and in vivo investigations, miR-215 was pinpointed as a negative feedback regulator, working against the TIC-promoting effects of hypoxia. Furthermore, we could single out LGR5, a bona fide marker of non-neoplastic intestinal stem cells, as a downstream target of hypoxia/miR-215 signaling. The strong tumor- and TIC-suppressor potential of miR-215 and the regulatory role of the hypoxia/miR-215/LGR5 axis may thus represent interesting points of attack for the development of innovative anti-CSC therapy approaches.
AB - Cancer stem cells, also known as tumor-initiating cells (TICs), are a population of aggressive and self-renewing cells that are responsible for the initiation and progression of many cancers, including colorectal carcinoma. Intratumoral hypoxia, i.e. reduced oxygen supply following uncontrolled proliferation of cancer cells, is thought to support TIC activity by inducing specific hypoxia-responsive mechanisms that are not yet entirely understood. Using previously established and fully characterized patient-derived TIC cultures, we could observe increased sphere and colony formation under hypoxic conditions. Mechanistically, microRNA (miRNA)-profiling experiments allowed us to identify miR-215 as one of the main hypoxia-induced miRNAs in primary colon TICs. Through stable overexpression of miR-215, followed by a set of functional in vitro and in vivo investigations, miR-215 was pinpointed as a negative feedback regulator, working against the TIC-promoting effects of hypoxia. Furthermore, we could single out LGR5, a bona fide marker of non-neoplastic intestinal stem cells, as a downstream target of hypoxia/miR-215 signaling. The strong tumor- and TIC-suppressor potential of miR-215 and the regulatory role of the hypoxia/miR-215/LGR5 axis may thus represent interesting points of attack for the development of innovative anti-CSC therapy approaches.
KW - Colon cancer stem cell
KW - Hypoxia
KW - LGR5
KW - miR-215
KW - microRNA
UR - http://www.scopus.com/inward/record.url?scp=85062214471&partnerID=8YFLogxK
U2 - 10.1016/j.canlet.2019.02.030
DO - 10.1016/j.canlet.2019.02.030
M3 - Article
C2 - 30790680
AN - SCOPUS:85062214471
SN - 0304-3835
VL - 450
SP - 32
EP - 41
JO - Cancer Letters
JF - Cancer Letters
ER -