Abstract A17: miRNA silencing in malignant melanoma: Mechanisms, regulation, and potential implications
2010
Metastatic melanoma is a devastating disease with limited treatment options. miRNAs are small RNA species within cells whose aberrant expression has been implicated in cancerous transformation, in some cases by a mechanism of cellular de-differentiation. The role of miRNA in melanoma is still not known. We recently observed that the expression of miRNAs from a large intergenic miRNA cluster is significantly down-regulated or absent in melanoma cell lines in comparison to normal melanocytes. This cluster resides within a parentally imprinted chromosomal region implicated in development and differentiation, and the miRNAs in this region are normally expressed selectively only in brain and skin. This chromosomal region was shown to be involved in the pathogenesis of ovarian carcinoma, and several of the miRNAs within it were shown to have tumor suppressor functions in other cellular models. Our results demonstrate that in some melanoma cell lines, there is a chromosomal deletion or loss of heterozygosity in the cis-acting differentially-methylated regulatory region of this cluster. Conversely, in other cell lines we were able to re-express some of these miRNAs using epigenetic modifiers (de-methylating agents and histone de-acetylase inhibitors), suggesting that epigenetic aberrations take part in their silencing. We are now assessing whether miRNA re-expression or ectopic expression decreases the tumorigenic and metastatic potential of melanoma cells. Our results suggest that aberrant regulation of this chromosomal region has a role in the pathogenesis of melanoma, and may even lead, in the future, to the development of new therapeutic strategies and bio-markers in this yet incurable disease. Citation Information : Clin Cancer Res 2010;16(7 Suppl):A17
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