Vimentin-mediated regulation of cell motility through modulation of beta4 integrin protein levels in oral tumor derived cells |
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| Affiliation: | 1. Cancer Research Institute (CRI), Advanced Centre for Treatment, Research and Education in Cancer (ACTREC), Tata Memorial Centre (TMC), Kharghar, Navi Mumbai, India;2. Gade Laboratory for Pathology, Institute of Clinical Medicine, University of Bergen, Norway;3. Department of Pathology, Haukeland University Hospital, Bergen, Norway;4. Surgical Oncology, Head and Neck Unit, Tata Memorial Hospital (TMH), Parel, Mumbai, India;5. Department of Pathology, Tata Memorial Hospital (TMH), Parel, Mumbai, India;6. Laboratory of Neurochemistry, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892, USA;1. Department of Anatomy and Developmental Biology, Monash University, Clayton, VIC 3800, Australia;2. Murdoch Childrens Research Institute, The Royal Children’s Hospital, Parkville, VIC 3052, Australia;3. Sunnybrook Research Institute, Department of Immunology, University of Toronto, Toronto, ON M4N 3M5, Canada;4. California Institute for Regenerative Medicine, San Francisco, CA 94107, USA;5. Materials Science and Engineering, Commonwealth Scientific and Industrial Research Organisation, Clayton, VIC 3168, Australia;6. Australian Regenerative Medicine Institute, Monash University, Clayton, VIC 3800, Australia;7. Department of Paediatrics, University of Melbourne, Parkville, VIC 3050, Australia;1. Department of Dermatology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 162-8582, Japan;2. Research Laboratories, KOSÉ Corporation, 48-18, Sakae-cho, Kita-ku, Tokyo 114-0005, Japan;3. Department of Dermatology, National Center for Child Health and Development, 2-10-1, Okura, Setagaya-ku, Tokyo 157-8535, Japan;4. Department of Dermatology, School of Medicine, Faculty of Medicine, Toho University, 6-11-1, Omori-nishi, Ota-ku, Tokyo 143-8541, Japan;3. Markey Cancer Center, University of Kentucky, Lexington, Kentucky 40506-0509;4. Departments of Molecular and Cellular Biochemistry, University of Kentucky, Lexington, Kentucky 40506-0509;5. Departments of Toxicology and Cancer Biology, University of Kentucky, Lexington, Kentucky 40506-0509;6. Departments of Pathology and Laboratory Medicine, University of Kentucky, Lexington, Kentucky 40506-0509 |
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| Abstract: | 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 β4 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 β4 integrin adhesion-blocking (ASC-8) antibody or downregulation of β4 integrin in vimentin knockdown background. Interestingly, plectin which associates with α6β4 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 β4 integrin and plectin. Moreover, an inverse association was observed between vimentin expression and β4 integrin in oral squamous cell carcinoma (OSCC). Collectively, our results show a novel role of vimentin in modulating cell motility by destabilizing β4 integrin-mediated adhesive interactions. Further, vimentin-β4 integrin together may prove to be useful markers for prognostication of human oral cancer. |
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