title: DNA methylation-induced E-cadherin silencing is correlated with the clinicopathological features of melanoma.
abstract: E-cadherin, a calcium-dependent cell-cell adhesion molecule, has an important role in epithelial cell function, maintenance of tissue architecture and cancer suppression. Loss of E-cadherin promotes tumor metastatic dissemination and predicts poor prognosis. The present study investigated the clinicopathological significance of E-cadherin expression in cutaneous, mucosal and uveal melanoma related to epigenetic mechanisms that may contribute to E-cadherin silencing. E-cadherin expression was reduced in 55/130 cutaneous (42.3%), 49/82 mucosal (59.7%) and 36/64 uveal (56.2%) melanoma samples as compared to normal skin controls and was inversely associated with promoter methylation. Of the 10 different CpG sites studied (nt 863, 865, 873, 879, 887, 892, 901, 918, 920 and 940), two sites (nt 892 and 940) were 90-100% methylated in all the melanoma specimens examined and the other ones were partially methylated (range, 53-86%). In contrast, the methylation rate of the E-cadherin gene was low in normal tissues (range, 5-24%). In all the three types of melanoma studied, a significant correlation was found between reduced levels of E-cadherin and reduced survival, high mitotic index and metastasis, accounting for the predilection of lymph nodal localization. In cutaneous and mucosal melanoma, low E-cadherin expression was positively correlated also with head/neck localization and ulceration. A high frequency of reduced E-cadherin levels occurred in choroid melanomas. In vitro experiments showed that E-cadherin transcription was restored following 5-aza-2'-deoxycytidine (5-aza-dC) treatment or DNMT1 silencing and was negatively correlated with the invasive potential of melanoma cells. The significant relationship between E-cadherin silencing and several poor prognostic factors indicates that this adhesion molecule may play an important role in melanomagenesis. Therefore, the inverse association of E-cadherin expression with promoter methylation raises the intriguing possibility that reactivation of E-cadherin expression through promoter demethylation may represent a potential therapeutic strategy for the treatment of melanoma.
authors.affiliation: Department of Clinical and Experimental Medicine, Azienda Policlinico Universitario G. Martino, Messina, Italy.
authors.forename: Mario
authors.initials: M
authors.lastname: Venza
authors.affiliation: Department of Clinical and Experimental Medicine, Azienda Policlinico Universitario G. Martino, Messina, Italy.
authors.forename: Maria
authors.initials: M
authors.lastname: Visalli
authors.affiliation: Department of Clinical and Experimental Medicine, Azienda Policlinico Universitario G. Martino, Messina, Italy.
authors.forename: Teresa
authors.initials: T
authors.lastname: Catalano
authors.affiliation: Department of Human Pathology of Adult and Developmental Age 'Gaetano Barresi', Azienda Policlinico Universitario G. Martino, Messina, Italy.
authors.forename: Carmelo
authors.initials: C
authors.lastname: Biondo
authors.affiliation: Department of Human Pathology of Adult and Developmental Age 'Gaetano Barresi', Azienda Policlinico Universitario G. Martino, Messina, Italy.
authors.forename: Concetta
authors.initials: C
authors.lastname: Beninati
authors.affiliation: Department of Clinical and Experimental Medicine, Azienda Policlinico Universitario G. Martino, Messina, Italy.
authors.forename: Diana
authors.initials: D
authors.lastname: Teti
authors.affiliation: Department of Clinical and Experimental Medicine, Azienda Policlinico Universitario G. Martino, Messina, Italy.
authors.forename: Isabella
authors.initials: I
authors.lastname: Venza
mesh_terms: D015703:Antigens, CD; D015820:Cadherins / Q000235:genetics*; D045744:Cell Line, Tumor; D019175:DNA Methylation; D015536:Down-Regulation; D044127:Epigenesis, Genetic; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing; D006801:Humans; D008297:Male; D008545:Melanoma / Q000235:genetics / Q000473:pathology*; D009092:Mucous Membrane / Q000473:pathology*; D009362:Neoplasm Metastasis; D011401:Promoter Regions, Genetic; D017422:Sequence Analysis, DNA; D012878:Skin Neoplasms / Q000235:genetics / Q000473:pathology*; D016019:Survival Analysis; D014604:Uveal Neoplasms / Q000235:genetics / Q000473:pathology*; D000098943:Uveal Melanoma
chemical_list: D015703:Antigens, CD; C513384:CDH1 protein, human; D015820:Cadherins