title: Vimentin-mediated regulation of cell motility through modulation of beta4 integrin protein levels in oral tumor derived cells.
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.
authors.affiliation: Cancer Research Institute (CRI), Advanced Centre for Treatment, Research and Education in Cancer (ACTREC), Tata Memorial Centre (TMC), Kharghar, Navi Mumbai, India.
authors.forename: Crismita
authors.initials: C
authors.lastname: Dmello
authors.affiliation: Cancer Research Institute (CRI), Advanced Centre for Treatment, Research and Education in Cancer (ACTREC), Tata Memorial Centre (TMC), Kharghar, Navi Mumbai, India.
authors.forename: Sharada
authors.initials: S
authors.lastname: Sawant
authors.affiliation: Cancer Research Institute (CRI), Advanced Centre for Treatment, Research and Education in Cancer (ACTREC), Tata Memorial Centre (TMC), Kharghar, Navi Mumbai, India.
authors.forename: Hunain
authors.initials: H
authors.lastname: Alam
authors.affiliation: Cancer Research Institute (CRI), Advanced Centre for Treatment, Research and Education in Cancer (ACTREC), Tata Memorial Centre (TMC), Kharghar, Navi Mumbai, India.
authors.forename: Prakash
authors.initials: P
authors.lastname: Gangadaran
authors.affiliation: Cancer Research Institute (CRI), Advanced Centre for Treatment, Research and Education in Cancer (ACTREC), Tata Memorial Centre (TMC), Kharghar, Navi Mumbai, India.
authors.forename: Richa
authors.initials: R
authors.lastname: Tiwari
authors.affiliation: Cancer Research Institute (CRI), Advanced Centre for Treatment, Research and Education in Cancer (ACTREC), Tata Memorial Centre (TMC), Kharghar, Navi Mumbai, India.
authors.forename: Harsh
authors.initials: H
authors.lastname: Dongre
authors.affiliation: Cancer Research Institute (CRI), Advanced Centre for Treatment, Research and Education in Cancer (ACTREC), Tata Memorial Centre (TMC), Kharghar, Navi Mumbai, India.
authors.forename: Neha
authors.initials: N
authors.lastname: Rana
authors.affiliation: Cancer Research Institute (CRI), Advanced Centre for Treatment, Research and Education in Cancer (ACTREC), Tata Memorial Centre (TMC), Kharghar, Navi Mumbai, India.
authors.forename: Sai
authors.initials: S
authors.lastname: Barve
authors.affiliation: Gade Laboratory for Pathology, Institute of Clinical Medicine, University of Bergen, Norway; Department of Pathology, Haukeland University Hospital, Bergen, Norway.
authors.forename: Daniela Elena
authors.initials: DE
authors.lastname: Costea
authors.affiliation: Surgical Oncology, Head and Neck Unit, Tata Memorial Hospital (TMH), Parel, Mumbai, India.
authors.forename: Davendra
authors.initials: D
authors.lastname: Chaukar
authors.affiliation: Department of Pathology, Tata Memorial Hospital (TMH), Parel, Mumbai, India.
authors.forename: Shubhada
authors.initials: S
authors.lastname: Kane
authors.affiliation: Laboratory of Neurochemistry, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Harish
authors.initials: H
authors.lastname: Pant
authors.affiliation: Cancer Research Institute (CRI), Advanced Centre for Treatment, Research and Education in Cancer (ACTREC), Tata Memorial Centre (TMC), Kharghar, Navi Mumbai, India. Electronic address: mvaidya@actrec.gov.in.
authors.forename: Milind
authors.initials: M
authors.lastname: Vaidya
mesh_terms: D057134:Antibodies, Neutralizing / Q000494:pharmacology; D002294:Carcinoma, Squamous Cell / Q000175:diagnosis / Q000235:genetics* / Q000378:metabolism / Q000401:mortality; D002448:Cell Adhesion; D015815:Cell Adhesion Molecules / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D002465:Cell Movement; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D022002:Hemidesmosomes / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure; D006801:Humans; D039663:Integrin beta4 / Q000235:genetics* / Q000378:metabolism; D007382:Intermediate Filaments / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure; D008297:Male; D008875:Middle Aged; D009062:Mouth Neoplasms / Q000175:diagnosis / Q000235:genetics* / Q000378:metabolism / Q000401:mortality; D009361:Neoplasm Invasiveness; D009367:Neoplasm Staging; D051190:Plectin / Q000235:genetics / Q000378:metabolism; D061251:Primary Cell Culture; D011379:Prognosis; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D016019:Survival Analysis; D014746:Vimentin / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D000097794:Kalinin
chemical_list: D057134:Antibodies, Neutralizing; D015815:Cell Adhesion Molecules; D039663:Integrin beta4; D051190:Plectin; D034741:RNA, Small Interfering; D014746:Vimentin; D000097794:Kalinin; C059834:ITGB4 protein, human; C495332:PLEC protein, human
keywords: Cell adhesion; Migration; OSCC; Vimentin; β4 integrin