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.
Highlights
Claudins are transmembrane proteins involved in tight junction (TJ) formation and function within healthy epithelia, endothelia, and other tissues [1]
To determine whether claudin-2 overexpression may contribute to these outcomes, we first quantified prospectively the expression of CLDN2 mRNA in a homogenous population of primary tumor samples from patients with stage II/III colorectal cancer that were all treated with 5-FU–based adjuvant chemotherapy [14]
We performed a retrospective analysis of published datasets to determine whether CLDN2 mRNA expression level in primary colorectal tumors would be associated with specific disease outcomes
Summary
Claudins are transmembrane proteins involved in tight junction (TJ) formation and function within healthy epithelia, endothelia, and other tissues [1]. Claudins have been implicated in multiple biological processes, including the regulation of paracellular transport of solutes and water, the maintenance of epithelial tissue integrity, the maintenance of apico-basal polarity and the specification of morphology in embryos and tissues [2]. Their expression is altered in several cancer types, and a tumorpromoting role has been suggested for several claudin isoforms [3], including in colorectal cancer [4, 5]. Claudin promotes proliferation and anchorage-independent colony formation by human colorectal cancer cells in vitro, and increases tumor growth in xenografted mice [6]. Claudin-2 was recently shown to promote www.aacrjournals.org
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