The Role of E-Cadherin Down-Regulation in Oral Cancer: CDH1 Gene Expression and Epigenetic Blockage

Author(s): 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, M. Di Domenico

Journal Name: Current Cancer Drug Targets

Volume 14 , Issue 2 , 2014

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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 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.

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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Article Details

Year: 2014
Published on: 03 March, 2014
Page: [115 - 127]
Pages: 13
DOI: 10.2174/1568009613666131126115012
Price: $65

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