Tight junction protein claudin-2 promotes self-renewal of human colorectal cancer stem-like cells. Academic Article uri icon

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 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.

authors

  • Paquet-Fifield, Sophie
  • Koh, Shir Lin
  • Sim, Lesley C Lesley Cheng
  • Beyit, Laura Marie
  • Shembrey, Carolyn E
  • Moelck, Christina
  • Behrenbruch, Corina
  • Papin, Marina
  • Gironella, Meritxell
  • Guelfi, Sophie
  • Nasr, Ramona
  • Grillet, Fanny
  • Prudhomme, Michel
  • Bourgaux, Jean-François
  • Castells, Antoni
  • Pascussi, Jean-Marc
  • Heriot, Alexander G
  • Puisieux, Alain
  • Davis, Melissa J
  • Pannequin, Julie
  • Hill, Andrew F
  • Sloan, Erica K
  • Hollande, Frédéric

publication date

  • 2018