The Role of E-Cadherin Down-Regulation in Oral Cancer: CDH1 Gene Expression and Epigenetic Blockage
L. Lo Muzio,
S. De Maria,
A. De Rosa,
M. Di Domenico.
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 Ecadherin
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. Colocalization
of E-cadherin with epidermal growth factor (EGF) receptor (EGFR) 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 downregulation
and CDH1 promoter hypermethylation. In an in vitro model of OSCC the treatment with EGF caused
internalization and co-localization of E-cadherin with EGFR and the addition of demethylating agents increased E-cadherin
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.
Keywords: CDH1 methylation, clinical outcome, E-cadherin, EGFR, Epithelial Mesenchymal Transition, Methylation Specific
PCR, Oral squamous cell carcinoma, Real-Time PCR.
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