American Association for Cancer Research
00085472can171869-sup-185215_2_supp_4598595_p47x0l.xlsx (33.95 kB)

Supplemental Table S5 from Tight Junction Protein Claudin-2 Promotes Self-Renewal of Human Colorectal Cancer Stem-like Cells

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posted on 2023-03-31, 01:25 authored by Sophie Paquet-Fifield, Shir Lin Koh, Lesley Cheng, Laura M. Beyit, Carolyn Shembrey, Christina Mølck, Corina Behrenbruch, Marina Papin, Meritxell Gironella, Sophie Guelfi, Ramona Nasr, Fanny Grillet, Michel Prudhomme, Jean-Francois Bourgaux, Antoni Castells, Jean-Marc Pascussi, Alexander G. Heriot, Alain Puisieux, Melissa J. Davis, Julie Pannequin, Andrew F. Hill, Erica K. Sloan, Frédéric Hollande

This table contains identified self-renewal target genes for the three candidate miRNA experimentally tested in our study, along with their prediction score. Only those targets with prediction score >0.85 are included.


National Health and Medical Research Council



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 ALDHHigh CSCs and increased their proportion in colorectal cancer cell populations, limiting their differentiation and promoting the phenotypic transition of non-CSCs toward the ALDHHigh phenotype. Next-generation sequencing in ALDHHigh 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. Cancer Res; 78(11); 2925–38. ©2018 AACR.