The Role of E-Cadherin Down-Regulation in Oral Cancer: CDH1 Gene Expression and Epigenetic Blockage
G. Pannone, A. Santoro, A. Feola, P. Bufo, P. Papagerakis, L. Lo Muzio, S. Staibano, F. Ionna, F. Longo, R. Franco, G. Aquino, M. Contaldo, S. De Maria, R. Serpico, A. De Rosa, C. Rubini, S. Papagerakis, A. Giovane, V. Tombolini, A. Giordano, M. Caraglia and M. Di Domenico
Affiliation: Department of Biochemistry, Biophisics and General Patology, Second University of Naples, Via L. De Crecchio, 7, 80138 Naples, Italy.
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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