BACR3
The regulation of desmosomal cadherins in epithelial-mesenchymal transition
Min-Che Chen
Manchester Metropolitan University, Manchester, UK
Background
The desmosomal cadherins, desmocollin (Dsc) and desmoglein (Dsg), are transmembrane proteins forming desmosomal adhesion of adjacent cells with their extracellular domains. Dsc and Dsg both occur as at least three distinct isoforms that show tissue-specific expression patterns. Transgenic mice experiments suggest that different isoforms have roles in the regulation of epithelial differentiation, proliferation, and morphogenesis. However, little is known about Dsc2 and Dsg2, the most ubiquitous desmosomal cadherins. Epithelial-mesenchymal transition (EMT) is an indispensable mechanism during cancer invasion and metastasis, in which epithelial cells must down-regulate desmosomal adhesion to transform into mesenchymal cells.
Method
In this study, the role of Dsc2 and Dsg2 in hepatocyte growth factor/scatter factor (HGF/SF) induced EMT has been investigated by generation of stably expressing Dsc2 and Dsg2 clones of Madin-Darby canine kidney (MDCK) epithelial cells, followed by examination of their morphology, cell migration and invasion abilities. Anti-Dsc2 and anti-Dsc2 antibodies were used to study Dsc2 and Dsg2 functions in cell-cell interaction and EMT.
Results
Interestingly, unlike Dsc2-transfected MDCK cells, Dsg2-transfected MDCK cells display a mesenchymal phenotype in low cell density culture. Clones stably transfected with Dsg2 exhibit greater migration and invasion ability compared to non-transfected MDCK cells or Dsc2-transfected cells. Consistent with these findings, antibody blocking experiments demonstrate that anti-Dsg2 antibodies inhibit HGF/SF induced EMT. In contrast, anti-Dsc2 antibodies disrupt cell-cell interactions but do not inhibit EMT.
Conclusion
This study shows that Dsc2 and Dsg2 have different functions in EMT. Dsc2 maintains epithelial cell-cell adhesion, but Dsg2 promotes mesenchymal characteristics. These novel findings have established a mechanistic link between desmosomal cadherins and EMT, contributing to a potential target in prevention of metastasis via inhibition of Dsg2.
