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https://hdl.handle.net/2440/134875
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Type: | Journal article |
Title: | Tight junction protein claudin-2 promotes self-renewal of human colorectal cancer stem-like cells |
Author: | Paquet-Fifield, S. Koh, S.L. Cheng, L. Beyit, L.M. Shembrey, C. Mølck, C. Behrenbruch, C. Papin, M. Gironella, M. Guelfi, S. Nasr, R. Grillet, F. Prudhomme, M. Bourgaux, J.F. Castells, A. Pascussi, J.M. Heriot, A.G. Puisieux, A. Davis, M.J. Pannequin, J. et al. |
Citation: | Cancer Research, 2018; 78(11):2925-2938 |
Publisher: | American Association for Cancer Research |
Issue Date: | 2018 |
ISSN: | 0008-5472 1538-7445 |
Statement of Responsibility: | Sophie Paquet-Fifield ... Melissa J. Davis ... et. al |
Abstract: | Posttreatment recurrence of colorectal cancer, the third most lethal cancer worldwide, is often driven by a subpopulation of cancer stem cells (CSC). The tight junction (TJ) protein claudin-2 is overexpressed in human colorectal cancer, where it enhances cell proliferation, colony formation, and chemoresistance in vitro. While several of these biological processes are features of the CSC phenotype, a role for claudin-2 in the regulation of these has not been identified. Here, we report that elevated claudin-2 expression in stage II/III colorectal tumors is associated with poor recurrence free survival following 5-fluorouracil–based chemotherapy, an outcome in which CSCs play an instrumental role. In patient-derived organoids, primary cells, and cell lines, claudin-2 promoted colorectal cancer self-renewal in vitro and in multiple mouse xenograft models. Claudin-2 enhanced self-renewal of ALDH High CSCs and increased their proportion in colorectal cancer cell populations, limiting their differentiation and promoting the phenotypic transition of non-CSCs toward the ALDH High phenotype. Next-generation sequencing in ALDH High cells revealed that claudin-2 regulated expression of nine miRNAs known to control stem cell signaling. Among these, miR-222-3p was instrumental for the regulation of self-renewal by claudin-2, and enhancement of this self-renewal required activation of YAP, most likely upstream from miR-222-3p. Taken together, our results indicate that overexpression of claudin-2 promotes self-renewal within colorectal cancer stem-like cells, suggesting a potential role for this protein as a therapeutic target in colorectal cancer. Significance: Claudin-2-mediated regulation of YAP activity and miR-222-3p expression drives CSC renewal in colorectal cancer, making it a potential target for therapy. |
Keywords: | Colorectal Neoplasms |
Rights: | © 2018 AACR. |
DOI: | 10.1158/0008-5472.CAN-17-1869 |
Grant ID: | http://purl.org/au-research/grants/nhmrc/1049561 http://purl.org/au-research/grants/nhmrc/1069024 |
Published version: | http://dx.doi.org/10.1158/0008-5472.can-17-1869 |
Appears in Collections: | Medicine publications |
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