Claudin-2 expression increases tumorigenicity of colon cancer cells: role of epidermal growth factor receptor activation

Abstract

Claudin-2 is a unique member of the claudin family of transmembrane proteins as its expression is restricted to the leaky epithelium in vivo and correlates with epithelial leakiness in vitro. However, recent evidence suggests potential functions of claudin-2 that are relevant to neoplastic transformation and growth. In accordance here we report, based upon analysis of mRNA and protein expression using a total of 309 patient samples, that claudin-2 expression is significantly increased in colorectal cancer and correlates with cancer progression. We also report similar increases in claudin-2 expression in inflammatory bowel disease (IBD)-associated colorectal cancer. Most importantly, we demonstrate that the increased claudin-2 expression in colorectal cancer is causally associated with tumor growth as forced claudin-2 expression in colon cancer cells that do not express claudin-2 resulted in significant increases in cell proliferation, anchorage-independent growth, and tumor growth in vivo. We further show that the colonic microenvironment regulates claudin-2 expression in a manner dependent on signaling through the EGF receptor (EGFR), a key regulator of colon tumorigenesis. In addition, claudin-2 expression is specifically decreased in the colon of waved-2 mice, naturally deficient in EGFR activation. Furthermore, genetic silencing of claudin-2 expression in Caco-2 , a colon cancer cell line, prevents the EGF-induced increase in cell proliferation. Taken together, these results uncover a novel role for claudin-2 in promoting colon cancer, potentially via EGFR transactivation.

Autophagy Enhances Intestinal Epithelial Tight Junction Barrier Function by Targeting Claudin-2 Protein Degradation

“…Therefore, the role of claudin-2 in intestinal pathological processes has been attributed, in part, to increases in intestinal TJ permeability. In addition, the increase in claudin-2 expression has been implicated to play a role in IBD-associated dysplasia and colitisassociated carcinogenesis by promoting cell proliferation and tumorigenicity (48,49). Therefore, our findings are very important in view of defects in autophagy reported in IBD and autophagy regulation of paracellular permeability via claudin-2.…”

Hepatocyte Growth Factor Activator Inhibitor Type 1 Is a Suppressor of Intestinal Tumorigenesis

“…Upregulation of claudin-2 expression would further enhance epithelial permeability in Spint1-deleted Apc Min/þ mice, as this particular claudin correlates with epithelial leakiness (4,5). Moreover, claudin-2 is reported to be involved in colon tumorigenesis (37). Enhanced activation of Hgf and its specific receptor c-Met may also be an important mechanism for tumorigenesis enhanced by Hai-1/Spint1 loss, as HAI-1/SPINT1 is a potent inhibitor of major proHGF-activating proteases, HGF activator, matriptase, and hepsin (6,13,16), and important roles of HGF/c-MET in cancer progression have been established (38).…”

Phosphorylation of claudin-2 on serine 208 promotes membrane retention and reduces trafficking to lysosomes

“…In addition, claudin-2 has been reported in the central cilium (Larre et al, 2011) and in metastatic cells, to be present in integrin-based complexes (Tabariès et al, 2011). Aside from its role in promoting cation permeability at the tight junctions, it has been implicated in regulation of the rate of cell division and metastatic potential (Buchert et al, 2010;Dhawan et al, 2011).…”