title: Association of Notch4 with metastasis in human oral squamous cell carcinoma.
abstract: OBJECTIVE
  Despite the development of several therapeutic strategies in the past decades, clinicians have failed to improve the survival rate of oral squamous cell carcinoma patients due to the highly metastatic nature of the disease and its high recurrence rate. However, there is accumulating evidence that aberrant Notch4 expression has a critical role in tumorigenesis but its prognostic value and function in OSCC remains uncertain. This study therefore investigates (1) the expression of Notch4 and its downstream target, myelin associated glycoprotein (MAG) in tissue samples representative of different stages of OSCC with varied clinicopathological features and (2) the possible involvement of Notch4 in the proliferation and migration of OSCC cells.
  
  
  METHODS
  Sixty patients reported positive for OSCC were obtained along with the clinicopathological parameters and we performed immunohistochemistry, western blotting and RT-PCR for Notch4 and MAG expression. Further, the metastatic role of Notch4 was analyzed in the HSC-3 cell line by cell proliferation and migration assays.
  
  
  RESULTS
  Our findings reveal that Notch4 and MAG expression are significantly upregulated in specifically late stages of OSCC tumor sections and perineural invasion (PNI) positive cases. In addition, depletion of Notch4 by siRNA inhibited the proliferative and migratory ability of the highly metastatic HSC-3 OSCC cells.
  
  
  CONCLUSIONS
  Our study indicates that the aberrant activation of Notch4 promotes OSCC metastasis through perineural spread and ascertains its value as a significant prognostic marker and potential therapeutic target to treat this highly aggressive malignancy.
authors.affiliation: Department of Genetic Engineering, School of Bioengineering, SRM University, Kattankulathur 603203, India.
authors.forename: Harishankar
authors.initials: H
authors.lastname: Mk
authors.affiliation: Department of Human Biology, Faculty of Health Sciences, University of Cape Town, Cape Town, , South Africa.
authors.forename: Sharon
authors.initials: S
authors.lastname: Prince
authors.affiliation: Department of Oral and Maxillofacial Surgery, Karpaga Vinayaga Institute of Dental Sciences, Kancheepuram 603308, India.
authors.forename: A Mathan
authors.initials: AM
authors.lastname: Mohan
authors.affiliation: Department of Oral and Maxillofacial Surgery, Karpaga Vinayaga Institute of Dental Sciences, Kancheepuram 603308, India.
authors.forename: K Vinod
authors.initials: KV
authors.lastname: Krishnan
authors.affiliation: Department of Genetic Engineering, School of Bioengineering, SRM University, Kattankulathur 603203, India. Electronic address: adevipradeep@gmail.com.
authors.forename: Arikketh
authors.initials: A
authors.lastname: Devi
mesh_terms: D002294:Carcinoma, Squamous Cell / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008297:Male; D008875:Middle Aged; D009062:Mouth Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D018992:Myelin-Associated Glycoprotein / Q000378:metabolism; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D000074562:Receptor, Notch4; D051880:Receptors, Notch / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation
chemical_list: C115082:MAG protein, human; D018992:Myelin-Associated Glycoprotein; C106075:NOTCH4 protein, human; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger; D000074562:Receptor, Notch4; D051880:Receptors, Notch
keywords: MAG; Metastatic marker; Notch4; OSCC; Perineural invasion