Vimentin-mediated regulation of cell motility through modulation of beta4 integrin protein levels in oral tumor derived cells.

Vimentin expression correlates well with migratory and invasive potential of the carcinoma cells. The molecular mechanism by which vimentin regulates cell motility is not yet clear. Here, we addressed this issue by depleting vimentin in oral squamous cell carcinoma derived cell line. Vimentin knockdown cells showed enhanced adhesion and spreading to laminin-5. However, we found that they were less invasive as compared to the vector control cells. In addition, signaling associated with adhesion behavior of the cell was increased in vimentin knockdown clones. These findings suggest that the normal function of beta4 integrin as mechanical adhesive device is enhanced upon vimentin downregulation. As a proof of principle, the compromised invasive potential of vimentin depleted cells could be rescued upon blocking with beta4 integrin adhesion-blocking (ASC-8) antibody or downregulation of beta4 integrin in vimentin knockdown background. Interestingly, plectin which associates with alpha6beta4 integrin in the hemidesmosomes, was also found to be upregulated in vimentin knockdown clones. Furthermore, experiments on lysosome and proteasome inhibition revealed that perhaps vimentin regulates the turnover of beta4 integrin and plectin. Moreover, an inverse association was observed between vimentin expression and beta4 integrin in oral squamous cell carcinoma (OSCC). Collectively, our results show a novel role of vimentin in modulating cell motility by destabilizing beta4 integrin-mediated adhesive interactions. Further, vimentin-beta4 integrin together may prove to be useful markers for prognostication of human oral cancer.