The Role Of E-Cadherin Down-Regulation In Oral Cancer: Cdh1 Gene Expression And Epigenetic Blockage

Background: The prognosis of the oral squamous cell carcinoma (OSCC) patients remains very poor, mainly due to their high propensity to invade and metastasize. E-cadherin reduced expression occurs in the primary step of oral tumour progression and gene methylation is a mode by which the expression of this protein is regulated in cancers. In this perspective, we investigated E-cadherin gene (CDH1) promoter methylation status in OSCC and its correlation with E-cadherin protein expression, clinicopathological characteristics and patient outcome.
 Methods: Histologically proven OSCC and paired normal mucosa were analyzed for CDH1 promoter methylation status and E-cadherin protein expression by methylation-specific polymerase chain reaction and immunohistochemistry. Co-localization of E-cadherin with EGF receptor was evidenced by confocal microscopy and by immunoprecipitation analyses.
 Results: This study indicated E-cadherin protein down-regulation in OSCC associated with protein delocalization from membrane to cytoplasm. Low E-cadherin expression correlated to aggressive, poorly differentiated, high grade carcinomas and low patient survival. Moreover, protein down-regulation appeared to be due to E-cadherin mRNA down-regulation and CDH1 promoter hypermethylation. In a model in vitro of OSCC the treatment with epidermal growth factor (EGF) caused internalization and co-localization of E-cadherin with EGF receptor (EGFR) and the addition of demethylating agents increased E-cadherin expression.
 Conclusion: Low E-Cadherin expression is a negative prognostic factor of OSCC and is likely due to the hypermethylation of CDH1 promoter. The delocalization of E-cadherin from membrane to cytoplasm could be also due to the increased expression of EGFR in OSCC and the consequent increase of E-cadherin co-internalization with EGFR.