Clinical Significance of Altered Expression of β-Catenin and E-Cadherin in Oral Dysplasia and Cancer: Potential Link with ALCAM Expression

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 b -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 beta-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 beta-catenin was determined using western blot, confocal microscopy and RT-PCR analysis in oral cancer cells. Results: Significant loss of membranous E-cadherin and beta-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 beta-catenin membrane loss and ALCAM/beta-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 beta-catenin both at the transcript and protein levels. Conclusions: Losses of E-cadherin and beta-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 beta-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.