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NT5E (CD73) is epigenetically regulated in malignant melanoma and associated with metastatic site specificity.

Abstract：

BACKGROUND:Novel prognostic biomarkers and therapeutic strategies are urgently required for malignant melanoma. Ecto-5-prime-nucleotidase (NT5E; CD73) overexpression has been reported in several human cancers. The mechanism(s) underlying deregulated expression and the clinical consequences of changes in expression are not known. METHODS:We used RT-PCR, qPCR, methylation-specific PCR and pyrosequencing to analyse expression and regulation of NT5E in malignant melanoma cell lines and primary and metastatic melanomas. RESULTS:NT5E is subject to epigenetic regulation in melanoma. NT5E mRNA is downregulated by methylation-dependent transcriptional silencing in the melanoma cell lines SKMel2, SKMel23, WM35, Mel501, Mel505 and C81-61 and expression is reactivated by azacytidine. In contrast, the CpG island is unmethylated and the gene expressed in cultured normal melanocytes. In clinical cases of melanoma, methylation in the NT5E CpG island occurs in both primary and metastatic melanomas and correlates with transcriptional downregulation of NT5E mRNA. Relapse with metastatic disease, particularly to the visceral sites and brain, is more common in primary melanomas lacking NT5E methylation. Primary melanomas with methylation in NT5E show limited metastatic potential or more commonly metastasise predominantly to nodal sites rather than viscera and brain (P=0.01). CONCLUSION:Deregulation of NT5E expression in melanoma occurs via epigenetic changes in the NT5E CpG island. Confirmation of our results in larger clinical series would support the candidacy of NT5E as a clinical biomarker in melanoma, which could be applied in both primary and relapsed disease. Inhibition of NT5E may have therapeutic potential in melanoma, particularly in patients with more aggressive disease metastatic to viscera or the brain.

journal_name

Br J Cancer

journal_title

British journal of cancer

authors

Wang H,Lee S,Nigro CL,Lattanzio L,Merlano M,Monteverde M,Matin R,Purdie K,Mladkova N,Bergamaschi D,Harwood C,Syed N,Szlosarek P,Briasoulis E,McHugh A,Thompson A,Evans A,Leigh I,Fleming C,Inman GJ,Hatzimichael E,

doi

10.1038/bjc.2012.95

subject

Has Abstract

pub_date

2012-04-10 00:00:00

pages

1446-52

issue

eissn

0007-0920

issn

1532-1827

pii

bjc201295

journal_volume

106

pub_type

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NT5E (CD73) is epigenetically regulated in malignant melanoma and associated with metastatic site specificity.