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. GiordanoM. Caraglia, M. Di Domenico

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish
Pages (from-to)115-127
Number of pages13
JournalCurrent Cancer Drug Targets
Volume14
Issue number2
DOIs
Publication statusPublished - 2014

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Neoplasm Genes
Mouth Neoplasms
Cadherins
Epigenomics
Down-Regulation
Gene Expression
Squamous Cell Carcinoma
Epidermal Growth Factor Receptor
Methylation
Proteins
Cytoplasm
Immunoprecipitation
Epidermal Growth Factor
Confocal Microscopy
Genes
Neoplasms
Membrane Proteins
Mucous Membrane
Immunohistochemistry

Keywords

  • CDH1 methylation
  • Clinical outcome
  • E-cadherin
  • EGFR
  • Epithelial Mesenchymal Transition
  • Methylation Specific PCR
  • Oral squamous cell carcinoma
  • Real-Time PCR

ASJC Scopus subject areas

  • Drug Discovery
  • Pharmacology
  • Cancer Research
  • Medicine(all)

Cite this

Pannone, G., Santoro, A., Feola, A., Bufo, P., Papagerakis, P., Lo Muzio, L., ... Di Domenico, M. (2014). The role of E-cadherin down-regulation in oral cancer: CDH1 gene expression and epigenetic blockage. Current Cancer Drug Targets, 14(2), 115-127. https://doi.org/10.2174/1568009613666131126115012

The role of E-cadherin down-regulation in oral cancer : CDH1 gene expression and epigenetic blockage. / Pannone, G.; Santoro, A.; Feola, A.; Bufo, P.; Papagerakis, P.; Lo Muzio, L.; Staibano, S.; Ionna, F.; Longo, F.; Franco, R.; Aquino, G.; Contaldo, M.; De Maria, S.; Serpico, R.; De Rosa, A.; Rubini, C.; Papagerakis, S.; Giovane, A.; Tombolini, V.; Giordano, A.; Caraglia, M.; Di Domenico, M.

In: Current Cancer Drug Targets, Vol. 14, No. 2, 2014, p. 115-127.

Research output: Contribution to journalArticle

Pannone, G, Santoro, A, Feola, A, Bufo, P, Papagerakis, P, Lo Muzio, L, Staibano, S, Ionna, F, Longo, F, Franco, R, Aquino, G, Contaldo, M, De Maria, S, Serpico, R, De Rosa, A, Rubini, C, Papagerakis, S, Giovane, A, Tombolini, V, Giordano, A, Caraglia, M & Di Domenico, M 2014, 'The role of E-cadherin down-regulation in oral cancer: CDH1 gene expression and epigenetic blockage', Current Cancer Drug Targets, vol. 14, no. 2, pp. 115-127. https://doi.org/10.2174/1568009613666131126115012
Pannone, G. ; Santoro, A. ; Feola, A. ; Bufo, P. ; Papagerakis, P. ; Lo Muzio, L. ; Staibano, S. ; Ionna, F. ; Longo, F. ; Franco, R. ; Aquino, G. ; Contaldo, M. ; De Maria, S. ; Serpico, R. ; De Rosa, A. ; Rubini, C. ; Papagerakis, S. ; Giovane, A. ; Tombolini, V. ; Giordano, A. ; Caraglia, M. ; Di Domenico, M. / The role of E-cadherin down-regulation in oral cancer : CDH1 gene expression and epigenetic blockage. In: Current Cancer Drug Targets. 2014 ; Vol. 14, No. 2. pp. 115-127.
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AU - Pannone, G.

AU - Santoro, A.

AU - Feola, A.

AU - Bufo, P.

AU - Papagerakis, P.

AU - Lo Muzio, L.

AU - Staibano, S.

AU - Ionna, F.

AU - Longo, F.

AU - Franco, R.

AU - Aquino, G.

AU - Contaldo, M.

AU - De Maria, S.

AU - Serpico, R.

AU - De Rosa, A.

AU - Rubini, C.

AU - Papagerakis, S.

AU - Giovane, A.

AU - Tombolini, V.

AU - Giordano, A.

AU - Caraglia, M.

AU - Di Domenico, M.

PY - 2014

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N2 - 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.

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