1012

CDH13

cadherin 13;CDH13;cadherin 13

H-cadherin (heart)|T-cad|T-cadherin|cadherin 13, H-cadherin (heart)|cadherin-13|heart cadherin

16q23.3

protein-coding

Overexpression of T-cadherin (T-cad) transcripts occurs in approximately 50% of human hepatocellular carcinomas (HCCs). To elucidate T-cad functions in HCC, we examined T-cad protein expression in normal and tumoral human livers and hepatoma cell lines and investigated its influence on invasive potential of HCC using RNA interference silencing of T-cad expression in Mahlavu cells. Whereas T-cad expression was restricted to endothelial cells (EC) from large blood vessels in normal livers, it was up-regulated in sinusoidal EC from 8/15 invasive HCCs. Importantly, in three of them (38%) T-cad was detected in tumor cells within regions in which E-cadherin expression was absent. Among six hepatoma cell lines, only Mahlavu expressed T-cad but not E-cadherin. T-cad exhibited a globally punctuate distribution in quiescent Mahlavu and additionally it concentrated at the leading edge of migrating cells. Matrigel invasion assay revealed that Mahlavu possess a high invasive potential that was significantly inhibited by T-cad silencing. Wound healing and random motility assays demonstrated that inhibition of T-cad expression in Mahlavu significantly reduced their motility. We propose that T-cad expression in tumor cells might occur by cadherin-switching during epithelial-mesenchymal transition and may represent an additional mechanism contributing to HCC metastasis.

T-cadherin is gaining recognition as a determinant for the development of incipient invasive squamous cell carcinoma (SCC). However, effects of T-cadherin expression on the metastatic potential of SCC have not been studied. Here, using a murine model of experimental metastasis following tail vein injection of A431 SCC cells we report that loss of T-cadherin increased both the incidence and rate of appearance of lung metastases. T-cadherin-silenced SCC metastases were highly disordered with evidence of single cell dissemination away from main foci whereas SCC metastases overexpressing T-cadherin developed as compact, tightly organised sheets. SCC cell adhesion to vascular endothelial cells (EC) in culture was increased for T-cadherin-silenced SCC and decreased for T-cadherin-overexpressing SCC. Confocal microscopy showed that T-cadherin-silenced SCC adherent on EC display an elongated morphology with long thin extensions and a high degree of intercalation within the EC monolayer, whereas SCC overexpressing T-cadherin formed poorly-spread multicellular aggregates that remain on the outer surface of the EC monolayer. T-cadherin-deficient SCC or human keratinocyte cells exhibited increased transendothelial migration in vitro which could be attenuated in the presence of EGFR inhibitor gefitinib. Our data suggest that loss of T-cadherin can increase metastatic potential and aggressiveness of SCC, possibly due to facilitating arrest and extravasation through the vascular wall and/or more efficient establishment of metastases in the new microenvironment.