title: The role of E-cadherin down-regulation in oral cancer: CDH1 gene expression and epigenetic blockage.
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.
  
  
  CONCLUSIONS
  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.
authors.forename: G
authors.initials: G
authors.lastname: Pannone
authors.forename: A
authors.initials: A
authors.lastname: Santoro
authors.forename: A
authors.initials: A
authors.lastname: Feola
authors.forename: P
authors.initials: P
authors.lastname: Bufo
authors.forename: P
authors.initials: P
authors.lastname: Papagerakis
authors.forename: L
authors.initials: L
authors.lastname: Lo Muzio
authors.forename: S
authors.initials: S
authors.lastname: Staibano
authors.forename: F
authors.initials: F
authors.lastname: Ionna
authors.forename: F
authors.initials: F
authors.lastname: Longo
authors.forename: R
authors.initials: R
authors.lastname: Franco
authors.forename: G
authors.initials: G
authors.lastname: Aquino
authors.forename: M
authors.initials: M
authors.lastname: Contaldo
authors.forename: S
authors.initials: S
authors.lastname: De Maria
authors.forename: R
authors.initials: R
authors.lastname: Serpico
authors.forename: A
authors.initials: A
authors.lastname: De Rosa
authors.forename: C
authors.initials: C
authors.lastname: Rubini
authors.forename: S
authors.initials: S
authors.lastname: Papagerakis
authors.forename: A
authors.initials: A
authors.lastname: Giovane
authors.forename: V
authors.initials: V
authors.lastname: Tombolini
authors.forename: A
authors.initials: A
authors.lastname: Giordano
authors.forename: M
authors.initials: M
authors.lastname: Caraglia
authors.affiliation: Department of Biochemistry, Biophisics and General Patology, Second University of Naples, Via L. De Crecchio, 7, 80138 Naples, Italy. michele.caraglia@unina2.it.
authors.forename: M
authors.initials: M
authors.lastname: Di Domenico
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D015703:Antigens, CD; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology; D014408:Biomarkers, Tumor / Q000235:genetics* / Q000378:metabolism; D015820:Cadherins / Q000235:genetics* / Q000378:metabolism; D002294:Carcinoma, Squamous Cell / Q000235:genetics* / Q000378:metabolism / Q000401:mortality / Q000473:pathology; D016022:Case-Control Studies; D045744:Cell Line, Tumor; D019175:DNA Methylation / Q000187:drug effects; D015254:DNA Modification Methylases / Q000037:antagonists & inhibitors / Q000378:metabolism; D015536:Down-Regulation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D044127:Epigenesis, Genetic / Q000187:drug effects; D066246:ErbB Receptors / Q000378:metabolism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D020022:Genetic Predisposition to Disease; D006258:Head and Neck Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000401:mortality / Q000473:pathology; D006801:Humans; D007150:Immunohistochemistry; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D009062:Mouth Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000401:mortality / Q000473:pathology; D011379:Prognosis; D011401:Promoter Regions, Genetic; D021381:Protein Transport; D012333:RNA, Messenger / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D000077195:Squamous Cell Carcinoma of Head and Neck; D013997:Time Factors
chemical_list: D015703:Antigens, CD; D000964:Antimetabolites, Antineoplastic; D014408:Biomarkers, Tumor; C513384:CDH1 protein, human; D015820:Cadherins; D004791:Enzyme Inhibitors; D012333:RNA, Messenger; D015254:DNA Modification Methylases; C512478:EGFR protein, human; D066246:ErbB Receptors