title: Clinical significance of altered expression of β-catenin and E-cadherin in oral dysplasia and cancer: potential link with ALCAM expression.
abstract: BACKGROUND
  Perturbations in cell adhesion molecules are linked to alterations in cadherin-catenin complexes and likely play major roles in invasion and metastasis; their impact on early precancerous stages remains yet unknown. We showed ALCAM overexpression in early oral lesions and its cytoplasmic accumulation in oral squamous cell carcinoma (OSCC) to be a predictor of disease progression and poor prognosis. This study tested the hypothesis that alterations in E-cadherin and β -catenin expressions are early events in oral tumorigenesis, associated with disease prognosis, and correlate with perturbations in ALCAM expression.
  
  
  METHODS
  Expressions of E-cadherin and β-catenin were analyzed in the same cohort of 105 OSCCs, 76 oral lesions and 30 normal oral tissues by immunohistochemistry and correlated with clinicopathological parameters and prognosis. The effect of siRNA mediated ALCAM knockdown on E-cadherin and β -catenin was determined using western blot, confocal microscopy and RT-PCR analysis in oral cancer cells.
  
  
  RESULTS
  Significant loss of membranous E-cadherin and β-catenin expression was observed from normal, hyperplasia, dysplasia to OSCCs (p(trend) <0.001); and correlated with cytoplasmic ALCAM accumulation in OSCCs (p  = 0.006). Multivariate analysis revealed β-catenin membrane loss and ALCAM/β-catenin(nuclear/cytoplasmic) accumulation to be significant predictors for late clinical stage (p<0.001, OR = 8.7; p = 0.006, OR = 9.9, respectively) and nodal metastasis (p = 0.003, OR = 3.8; p = 0.025, OR = 3.4 respectively). Cox's regression showed E-cadherin membrane loss/ALCAM cytoplasmic expression [p<0.001; HR = 4.8] to be independent adverse prognosticators in OSCCs. siRNA mediated silencing of ALCAM resulted in concurrent increase in E-cadherin and β-catenin both at the transcript and protein levels.
  
  
  CONCLUSIONS
  Losses of E-cadherin and β-catenin expressions are early events in oral tumorigenesis; their associations with aggressive tumor behavior and disease recurrence underscore their potential as prognostic markers. Correlation of loss of E-cadherin and β-catenin with cytoplasmic ALCAM accumulation both in vitro and in in vivo suggests that these dynamic changes in cell adhesion system may play pivotal role in oral cancer.
authors.affiliation: Alex and Simona Shnaider Laboratory in Molecular Oncology, Department of Pathology and Laboratory Medicine, Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada.
authors.forename: Jatinder
authors.initials: J
authors.lastname: Kaur
authors.forename: Meenakshi
authors.initials: M
authors.lastname: Sawhney
authors.forename: Siddhartha
authors.initials: S
authors.lastname: DattaGupta
authors.forename: Nootan Kumar
authors.initials: NK
authors.lastname: Shukla
authors.forename: Anurag
authors.initials: A
authors.lastname: Srivastava
authors.forename: Paul G
authors.initials: PG
authors.lastname: Walfish
authors.forename: Ranju
authors.initials: R
authors.lastname: Ralhan
mesh_terms: D000328:Adult; D000368:Aged; D015703:Antigens, CD / Q000235:genetics / Q000378:metabolism*; D015820:Cadherins / Q000235:genetics / Q000378:metabolism*; D002294:Carcinoma, Squamous Cell / Q000378:metabolism* / Q000401:mortality; D015816:Cell Adhesion Molecules, Neuronal / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D018450:Disease Progression; D005260:Female; D005326:Fetal Proteins / Q000235:genetics / Q000378:metabolism*; D015870:Gene Expression; D055785:Gene Knockdown Techniques; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D009062:Mouth Neoplasms / Q000378:metabolism* / Q000401:mortality; D015999:Multivariate Analysis; D011230:Precancerous Conditions / Q000378:metabolism* / Q000473:pathology; D034741:RNA, Small Interfering / Q000235:genetics; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism*; D020410:Activated-Leukocyte Cell Adhesion Molecule
chemical_list: D015703:Antigens, CD; D015820:Cadherins; D015816:Cell Adhesion Molecules, Neuronal; D005326:Fetal Proteins; D034741:RNA, Small Interfering; D051176:beta Catenin; C105613:ALCAM protein, human; D020410:Activated-Leukocyte Cell Adhesion Molecule; C513384:CDH1 protein, human; C495270:CTNNB1 protein, human