title: Vimentin regulates differentiation switch via modulation of keratin 14 levels and their expression together correlates with poor prognosis in oral cancer patients.
abstract: Vimentin is an intermediate filament protein, predominantly expressed in cells of mesenchymal origin, although its aberrant expression is seen in many carcinomas during epithelial mesenchymal transition. In cancer, vimentin expression is associated with the transition from a more differentiated epithelial phenotype to a dedifferentiated state. In view of the perceived role of keratins (Ks) as regulators of differentiation in epithelia, it was important to understand whether vimentin modulates differentiation through the reprogramming of keratins, in transformed cells. To address this, vimentin was stably downregulated in oral cancer derived cells. Further, global keratin profiling was performed after high salt keratin extraction. K5/K14 pair was found to be significantly downregulated, both at protein and mRNA levels upon vimentin downregulation. The previous study from our laboratory has shown a role of the K5/K14 pair in proliferation and differentiation of squamous epithelial cells. Vimentin depleted cells showed an increase in the differentiation state, marked by an increase in the levels of differentiation specific markers K1, involucrin, filaggrin and loricrin while its proliferation status remained unchanged. Rescue experiments with the K5/K14 pair overexpressed in vimentin knockdown background resulted in decreased differentiation state. ΔNp63 emerged as one of the indirect targets of vimentin, through which it modulates the expression levels of K5/K14. Further, immunohistochemistry showed a significant correlation between high vimentin-K14 expression and recurrence/poor survival in oral cancer patients. Thus, in conclusion, vimentin regulates the differentiation switch via modulation of K5/K14 expression. Moreover, vimentin-K14 together may prove to be the novel markers for the 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.|Homi Bhabha National Institute, Training school complex, Anushakti Nagar, 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.|Homi Bhabha National Institute, Training school complex, Anushakti Nagar, 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: Saie
authors.initials: S
authors.lastname: Mogre
authors.affiliation: Cancer Research Institute (CRI), Advanced Centre for Treatment, Research and Education in Cancer (ACTREC), Tata Memorial Centre (TMC), Kharghar, Navi Mumbai, India.|Homi Bhabha National Institute, Training school complex, Anushakti Nagar, 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: Zinia
authors.initials: Z
authors.lastname: D'Souza
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: Manish
authors.initials: M
authors.lastname: Narkar
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: Rahul
authors.initials: R
authors.lastname: Thorat
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: Komal
authors.initials: K
authors.lastname: Patil
authors.affiliation: Homi Bhabha National Institute, Training school complex, Anushakti Nagar, Mumbai, India.|Surgical Oncology, Head and Neck Unit, Tata Memorial Hospital (TMH), Parel, Mumbai, India.
authors.forename: Devendra
authors.initials: D
authors.lastname: Chaukar
authors.affiliation: Homi Bhabha National Institute, Training school complex, Anushakti Nagar, Mumbai, India.|Department of Pathology, Tata Memorial Hospital (TMH), Parel, Mumbai, India.
authors.forename: Shubhada
authors.initials: S
authors.lastname: Kane
authors.affiliation: Cancer Research Institute (CRI), Advanced Centre for Treatment, Research and Education in Cancer (ACTREC), Tata Memorial Centre (TMC), Kharghar, Navi Mumbai, India.|Homi Bhabha National Institute, Training school complex, Anushakti Nagar, Mumbai, India.
authors.forename: Milind
authors.initials: M
authors.lastname: Vaidya
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000235:genetics*; D045744:Cell Line, Tumor; D015536:Down-Regulation; D005260:Female; D000091344:Filaggrin Proteins; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D053547:Keratin-14 / Q000235:genetics* / Q000378:metabolism; D053555:Keratin-5 / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D009062:Mouth Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000401:mortality / Q000473:pathology; D009364:Neoplasm Recurrence, Local / Q000235:genetics* / Q000378:metabolism / Q000401:mortality / Q000473:pathology; D011379:Prognosis; D051880:Receptors, Notch / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism; D014746:Vimentin / Q000235:genetics* / Q000378:metabolism
chemical_list: C000717249:FLG protein, human; D000091344:Filaggrin Proteins; D053547:Keratin-14; D053555:Keratin-5; D051880:Receptors, Notch; C115051:TP63 protein, human; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; D014746:Vimentin