title: Correlation of protease-activated receptor-1 with differentiation markers in squamous cell carcinoma of the head and neck and its implication in lymph node metastasis.
abstract: OBJECTIVE
  Protease-activated receptor-1 (PAR-1) is a G-protein-coupled receptor that contributes to multiple signal transduction pathways. Although the functions of PAR-1 in many normal cells, such as platelets and astrocytes, have been well studied, its roles in cancer progression and metastasis have not been fully elucidated, and studies to date appear contradictory.
  
  
  METHODS
  To clarify the function of PAR-1 in metastasis of squamous cell carcinoma of the head and neck (SCCHN), we examined PAR-1 expression in clinical specimens by immunohistochemistry and in SCCHN cell lines by immunoblotting. Furthermore, par-1 cDNA-transfected SCCHN cell lines were also used to verify PAR-1-mediated pathway.
  
  
  RESULTS
  The metastatic tumors showed a lower percentage of PAR-1-positive cells (46%) and lower levels of PAR-1 expression (median weight index = 10) than node negative primary tumors (80% and median weight index = 60, respectively). In addition, expression level of PAR-1 positively correlated with levels of keratinocyte differentiation markers keratin-1, -10, and -11. Additional studies using sense and antisense par-1 cDNA-transfected SCCHN cell lines illustrated that the presence of PAR-1 was required for the expression of involucrin, a keratinocyte differentiation marker. PAR-1 expression also contributes to activation of the mitogen-activated protein kinase (MAPK) pathway. Blocking MAPK activation by a mitogen-activated protein/extracellular signal-regulated kinase inhibitor, not by a phosphatidylinositol 3'-kinase inhibitor, reduced level of involucrin, suggesting that regulation of involucrin by PAR-1 is partially through the MAPK signaling pathway.
  
  
  CONCLUSIONS
  Our study suggests that PAR-1 signaling induces differentiation markers in SCCHN cells, and its expression is conversely correlated with cervical lymph node metastasis.
authors.affiliation: Department of Hematology-Oncology, Emory University Winship Cancer Institute, Atlanta, Georgia 30322, USA.
authors.forename: Xin
authors.initials: X
authors.lastname: Zhang
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Hunt
authors.forename: Doug P
authors.initials: DP
authors.lastname: Landsittel
authors.forename: Susan
authors.initials: S
authors.lastname: Muller
authors.forename: Karen
authors.initials: K
authors.lastname: Adler-Storthz
authors.forename: Robert L
authors.initials: RL
authors.lastname: Ferris
authors.forename: Dong M
authors.initials: DM
authors.lastname: Shin
authors.forename: Zhuo Georgia
authors.initials: ZG
authors.lastname: Chen
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor; D002294:Carcinoma, Squamous Cell / Q000175:diagnosis* / Q000378:metabolism; D002454:Cell Differentiation; D018076:DNA, Complementary / Q000235:genetics / Q000378:metabolism; D018450:Disease Progression; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D006258:Head and Neck Neoplasms / Q000175:diagnosis* / Q000378:metabolism; D006801:Humans; D007124:Immunoenzyme Techniques; D015603:Keratinocytes / Q000378:metabolism; D008207:Lymphatic Metastasis; D008297:Male; D008875:Middle Aged; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011498:Protein Precursors / Q000378:metabolism; D044463:Receptor, PAR-1 / Q000378:metabolism*; D015398:Signal Transduction; D014162:Transfection
chemical_list: D014408:Biomarkers, Tumor; D018076:DNA, Complementary; D004791:Enzyme Inhibitors; D020928:Mitogen-Activated Protein Kinases; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011498:Protein Precursors; D044463:Receptor, PAR-1; C032253:involucrin