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

Wang, H. et al. (2012) NT5E (CD73) is epigenetically regulated in malignant melanoma and associated with metastatic site specificity. British Journal of Cancer, 106(8), pp. 1446-1452. (doi: 10.1038/bjc.2012.95) (PMID:22454080) (PMCID:PMC3326678)

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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.

Item Type:Articles
Additional Information:The study was supported by Barts and the London Charity, The Brain Tumour Research Charity (BTRC), The Leng Foundation, The Medical Research Council and Tayside Tissue Bank. Eleftheria Hatzimichael is a scholar of The Hellenic Society of Haematology Foundation.
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Inman, Professor Gareth
Authors: Wang, H., Lee, S., Nigro, C. L., 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, G.J., Hatzimichael, E., Proby, C., and Crook, T.
College/School:College of Medical Veterinary and Life Sciences > School of Cancer Sciences
Journal Name:British Journal of Cancer
Publisher:Springer Nature
ISSN:0007-0920
ISSN (Online):1532-1827
Published Online:27 March 2012
Copyright Holders:Copyright © 2012 Cancer Research UK
First Published:First published in British Journal of Cancer 106:1446-1452
Publisher Policy:Reproduced under a Creative Commons License

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