P-Cadherin Regulates Intestinal Epithelial Cell Migration and Mucosal Repair, but Is Dispensable for Colitis Associated Colon Cancer

Abstract

Recurrent chronic mucosal inflammation, a characteristic of inflammatory bowel diseases (IBD), perturbs the intestinal epithelial homeostasis resulting in formation of mucosal wounds and, in most severe cases, leads to colitis-associated colon cancer (CAC). The altered structure of epithelial cell-cell adhesions is a hallmark of intestinal inflammation contributing to epithelial injury, repair, and tumorigenesis. P-cadherin is an important adhesion protein, poorly expressed in normal intestinal epithelial cells (IEC) but upregulated in inflamed and injured mucosa. The goal of this study was to investigate the roles of P-cadherin in regulating intestinal inflammation and CAC. P-cadherin expression was markedly induced in the colonic epithelium of human IBD patients and CAC tissues. The roles of P-cadherin were investigated in P-cadherin null mice using dextran sulfate sodium (DSS)-induced colitis and an azoxymethane (AOM)/DSS induced CAC. Although P-cadherin knockout did not affect the severity of acute DSS colitis, P-cadherin null mice exhibited faster recovery after colitis. No significant differences in the number of colonic tumors were observed in P-cadherin null and control mice. Consistently, the CRISPR/Cas9-mediated knockout of P-cadherin in human IEC accelerated epithelial wound healing without affecting cell proliferation. The accelerated migration of P-cadherin depleted IEC was driven by activation of Src kinases, Rac1 GTPase and myosin II motors and was accompanied by transcriptional reprogramming of the cells. Our findings highlight P-cadherin as a negative regulator of IEC motility in vitro and mucosal repair in vivo. In contrast, this protein is dispensable for IEC proliferation and CAC development.

Divergent roles of estrogen receptor subtypes in regulating estrogen-modulated colonic ion transports and epithelial repair

“…Since proliferation and migration of epithelial cells are critical for the restitution of injured intestinal epithelium ( 33 , 34 ), we examined the roles of ER subtypes in epithelial regeneration. PPT at 5 to 50 nM promoted proliferation of HCoEpiC ( Fig.…”

E-Cadherin Is Expressed in Epithelial Cells of the Choroid Plexus in Human and Mouse Brains

“…Accordingly, E-cadherin expression did not completely overlap with P-cadherin expression, as also shown in Table 4. P-cadherin is known to be poorly expressed in normal intestinal epithelial cells but upregulated in inflamed and injured mucosa [40]. Alteration of the expression of cadherins with aberrant P-cadherin expression is also known to be associated with co-expression or loss of E-cadherin expression in the gastrointestinal tract with neoplastic development or being repaired [41].…”

“…Alteration of the expression of cadherins with aberrant P-cadherin expression is also known to be associated with co-expression or loss of E-cadherin expression in the gastrointestinal tract with neoplastic development or being repaired [41]. Accordingly, uneven distribution of these cadherins may be related to the E-cadherin to P-cadherin switch, happening in inflamed or injured tissues [40][41][42]. A large-scale study including inflamed or injured choroid plexus tissues is required to prove the hypothesis.…”

Application Prospect of Induced Pluripotent Stem Cells in Organoids and Cell Therapy

“…With the change of modern lifestyle, the incidence of colitis has gradually increased, and the prone population is very wide, difficult to cure, and the cancer rate is high, so it’s listed as one of the modern difficult diseases by the World Health Organization [ 91 ]. Long-term colitis and adenomatous polyposis can lead to contractions, perforations, and even bowel cancer [ 92 , 93 , 94 , 95 , 96 , 97 , 98 , 99 , 100 ]. Colon cancer organoids can be derived based on iPSC technology [ 101 ].…”