P‐cadherin regulates intestinal epithelial repair, but is dispensable for colitis associated colon cancer development

Abstract

Recurrent chronic mucosal inflammation, which is characteristics for inflammatory bowel diseases (IBD), triggers significant changes in the intestinal epithelial homeostasis. These changes include leakiness of the gut barrier, formation of mucosal wounds and, in most severe cases, oncogenic transformation of colonic epithelium resulting in colitis‐associated colon cancer (CAC). Altered structure and dynamics of epithelial junctions is a hallmark of intestinal inflammation, mediating epithelial barrier injury and repair. P‐cadherin (gene name: CDH3) is an important component of adherens junctions (AJ), which is poorly expressed in normal intestinal epithelium, but could be induced in inflamed and injured mucosa. The goal of this his study was to investigate the roles of P‐cadherin in regulating intestinal inflammation, mucosal repair and CAC. P‐cadherin expression was markedly induced in the colonic epithelium of human IBD patients and CAC tissues. Roles of P‐cadherin in intestinal inflammation and tumorigenesis in vivo were investigated using a mouse strain with total P‐cadherin knockout. Dextran sulfate sodium (DSS)‐induced colitis was utilized to study mucosal inflammation, whereas CAC was established using a classical azoxymetane (AOM)/DSS model. Severity of acute DSS colitis was not affected by P‐cadherin knockout, however, P‐cadherin null mice exhibited faster recovery after DSS withdrawal indicating accelerated repair of injured mucosa. No significant differences in the number and size of colonic tumors was observed in P‐cadherin null and control mice after AOM/DSS induced CAC. Consistently, CRISPR/Cas9‐mediated knockout of P‐cadherin in SK‐CO15 and HCA7 human colonic epithelial cell lines accelerated epithelial wound healing without affecting cell proliferation. The faster migration of P‐cadherin depleted cells was associated with diminished cell‐matrix adhesions and increased cell spreading. Loss of P‐cadherin resulted in activation of Src kinase and the pro‐migratory phenotype of P‐cadherin depleted cell was reversed by pharmacological inhibition of Src. Furthermore, accelerated epithelial wound healing caused by loss of P‐cadherin was prevented by Rac1 inhibition. Our findings highlight P‐cadherin as a negative regulator of intestinal epithelial would heling in vitro and mucosal repair in vivo. By contrast, this AJ protein appears to be dispensable for intestinal epithelial cell proliferation and CAC development.

Adherens junction proteins on the move—From the membrane to the nucleus in intestinal diseases

“…Indeed, inflamed intestinal tissues in both humans and rodent models of IBD exhibit misexpression of several adhesion-associated proteins, a finding supported by genome-wide association studies of both Crohn’s disease (CD) and ulcerative colitis (UC), reviewed in ( Mehta et al, 2015 ). Interestingly, in inflamed intestinal mucosa of both active CD and UC, a phenomenon known as cadherin switching, where the expression of E-cadherin decreases and the expression of P-cadherin increases, is observed ( Sanders et al, 2000 ; Naydenov et al, 2022 ). While E-cadherin and P-cadherin are both classical cadherins and expressed in epithelial tissues, E-cadherin is the most highly expressed in healthy epithelial tissues in the gastrointestinal tract ( Sanders et al, 2000 ), while P-cadherin is poorly expressed ( Naydenov et al, 2022 ).…”

“…Interestingly, in inflamed intestinal mucosa of both active CD and UC, a phenomenon known as cadherin switching, where the expression of E-cadherin decreases and the expression of P-cadherin increases, is observed ( Sanders et al, 2000 ; Naydenov et al, 2022 ). While E-cadherin and P-cadherin are both classical cadherins and expressed in epithelial tissues, E-cadherin is the most highly expressed in healthy epithelial tissues in the gastrointestinal tract ( Sanders et al, 2000 ), while P-cadherin is poorly expressed ( Naydenov et al, 2022 ). Moreover, E-cadherin and P-cadherin have different adhesive properties and participate in different signaling activities, and thus the functional relevance of this switching in the inflamed intestinal mucosa remains to be determined ( Naydenov et al, 2022 ).…”

“…While E-cadherin and P-cadherin are both classical cadherins and expressed in epithelial tissues, E-cadherin is the most highly expressed in healthy epithelial tissues in the gastrointestinal tract ( Sanders et al, 2000 ), while P-cadherin is poorly expressed ( Naydenov et al, 2022 ). Moreover, E-cadherin and P-cadherin have different adhesive properties and participate in different signaling activities, and thus the functional relevance of this switching in the inflamed intestinal mucosa remains to be determined ( Naydenov et al, 2022 ). Regardless, the CDH1 and CDH3 loci, which encode E-cadherin and P-cadherin respectively, are among the various susceptibility loci implicated in IBD ( Sanders et al, 2000 ; Barrett et al, 2009 ; Mehta et al, 2015 ).…”