title: Loss of keratin 8 phosphorylation leads to increased tumor progression and correlates with clinico-pathological parameters of OSCC patients.
abstract: BACKGROUND
  Keratins are cytoplasmic intermediate filament proteins expressed in tissue specific and differentiation dependent manner. Keratins 8 and 18 (K8 and K18) are predominantly expressed in simple epithelial tissues and perform both mechanical and regulatory functions. Aberrant expression of K8 and K18 is associated with neoplastic progression, invasion and poor prognosis in human oral squamous cell carcinomas (OSCCs). K8 and K18 undergo several post-translational modifications including phosphorylation, which are known to regulate their functions in various cellular processes. Although, K8 and K18 phosphorylation is known to regulate cell cycle, cell growth and apoptosis, its significance in cell migration and/or neoplastic progression is largely unknown. In the present study we have investigated the role of K8 phosphorylation in cell migration and/or neoplastic progression in OSCC.
  
  
  RESULTS
  To understand the role of K8 phosphorylation in neoplastic progression of OSCC, shRNA-resistant K8 phospho-mutants of Ser73 and Ser431 were overexpressed in K8-knockdown human AW13516 cells (derived from SCC of tongue; generated previously). Wound healing assays and tumor growth in NOD-SCID mice were performed to analyze the cell motility and tumorigenicity respectively in overexpressed clones. The overexpressed K8 phospho-mutants clones showed significant increase in cell migration and tumorigenicity as compared with K8 wild type clones. Furthermore, loss of K8 Ser73 and Ser431 phosphorylation was also observed in human OSCC tissues analyzed by immunohistochemistry, where their dephosphorylation significantly correlated with size, lymph node metastasis and stage of the tumor.
  
  
  CONCLUSIONS
  Our results provide first evidence of a potential role of K8 phosphorylation in cell migration and/or tumorigenicity in OSCC. Moreover, correlation studies of K8 dephosphorylation with clinico-pathological parameters of OSCC patients also suggest its possible use in prognostication of human OSCC.
authors: Cancer Research Institute, Advanced Centre for Treatment, Research and Education in Cancer, Tata Memorial Centre, Kharghar, Navi Mumbai, India.
authors: Hunain
authors: H
authors: Alam
authors: Prakash
authors: P
authors: Gangadaran
authors: Amruta V
authors: AV
authors: Bhate
authors: Devendra A
authors: DA
authors: Chaukar
authors: Sharada S
authors: SS
authors: Sawant
authors: Richa
authors: R
authors: Tiwari
authors: Jyoti
authors: J
authors: Bobade
authors: Sadhana
authors: S
authors: Kannan
authors: Anil K
authors: AK
authors: D'cruz
authors: Shubhada
authors: S
authors: Kane
authors: Milind M
authors: MM
authors: Vaidya
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002294:Carcinoma, Squamous Cell / Q000378:metabolism* / Q000401:mortality / Q000473:pathology*; D002453:Cell Cycle; D002455:Cell Division; D002465:Cell Movement; D002478:Cells, Cultured; D005260:Female; D005455:Fluorescent Antibody Technique; D006801:Humans; D007124:Immunoenzyme Techniques; D053538:Keratin-18 / Q000235:genetics / Q000378:metabolism; D053533:Keratin-8 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D007668:Kidney / Q000166:cytology / Q000378:metabolism; D008207:Lymphatic Metastasis; D008297:Male; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D008875:Middle Aged; D009062:Mouth Neoplasms / Q000378:metabolism* / Q000401:mortality / Q000473:pathology*; D009367:Neoplasm Staging; D010766:Phosphorylation; D011379:Prognosis; D012333:RNA, Messenger / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D015996:Survival Rate
chemical_list: D053538:Keratin-18; D053533:Keratin-8; D012333:RNA, Messenger; D034741:RNA, Small Interfering