Loss of the desmosomal cadherin desmoglein-2 suppresses colon cancer cell proliferation through EGFR signaling

Abstract

Desmosomal cadherins mediate cell-cell adhesion in epithelial tissues and have been known to be altered in cancer. We have previously shown that one of the two intestinal epithelial desmosomal cadherins, desmocollin-2 (Dsc2) loss promotes colonic epithelial carcinoma cell proliferation and tumor formation. In this study we show that loss of the other intestinal desmosomal cadherin, desmoglein-2 (Dsg2) that pairs with Dsc2, results in decreased epithelial cell proliferation and suppressed xenograft tumor growth in mice. Dsg2-deficient cells demonstrated a compensatory increase in Dsc2 expression, and small interfering RNA-mediated loss of Dsc2 restored proliferation in Dsg2-deficient cells. Dsg2 downregulation inhibited epidermal growth factor receptor (EGFR) signaling and cell proliferation through altered phosphorylation of EGFR and downstream extracellular signal-regulated kinase activation in parallel with inhibited EGFR receptor internalization. Additionally, we demonstrated a central role of Dsc2 in controlling EGFR signaling and cell proliferation in intestinal epithelial cells. Consistent with these findings, analyses of human colon cancers demonstrated increased Dsg2 protein expression. Taken together, these data demonstrate that partner desmosomal cadherins Dsg2 and Dsc2 play opposing roles in controlling colonic carcinoma cell proliferation through differential effects on EGFR signaling.

Cell–Cell Adhesion and Cytoskeleton Tension Oppose Each Other in Regulating Tumor Cell Aggregation

“…Previous studies have demonstrated that desmosomes are affected by calcium influx into the cell (28) and that homophilic and heterophilic interactions between DSC and DSG proteins generate cell aggregation (29,30). It has also been shown that desmosomal protein expression may be altered during cancer development (31,32) and may regulate cell proliferation (33). We found that DSG2 is expressed in HCT116 cells (Fig.…”

Desmosome assembly, homeostasis, and desmosomal disease

“…Reduced expression of desmosomal cadherins, which may be responsible for the weakening of cell-cell adhesion observed in cancer cells, was observed in different tumors, such as skin, 151 head and neck, 152 lung, 153 breast, 154 and a variety of other epithelial malignancies, 155 including gastric 156 and colon 157 cancers. In one example, knockdown of Pkp3 in colon cancer cells promoted anchorage-independent growth and tumor growth in immunocompromised mice.…”