MicroRNA-26a Is Strongly Downregulated in Melanoma and Induces Cell Death through Repression of Silencer of Death Domains (SODD)

Abstract

Melanoma is an aggressive cancer that metastasizes rapidly, and is refractory to conventional chemotherapies. Identifying miRNAs that are responsible for this pathogenesis is therefore a promising means of developing new therapies. We identified miR-26a through microarray and qRT-PCR experiments as an miRNA that is strongly down-regulated in melanoma cell lines as compared to primary melanocytes. Treatment of cell lines with miR-26a mimic caused significant and rapid cell death compared to a negative control in most melanoma cell lines tested. In surveying targets of miR-26a, we found that protein levels of SMAD1 and BAG-4/SODD were strongly decreased in sensitive cells treated with miR-26a mimic compared to the control. The luciferase reporter assays further demonstrated that miR-26a can repress gene expression through the binding site in the 3′UTR of SODD. Knockdown of these proteins with siRNA showed that SODD plays an important role in protecting melanoma cells from apoptosis in most cell lines sensitive to miR-26a, while SMAD1 may play a minor role. Furthermore, transfecting cells with a miR-26a inhibitor increased SODD expression. Our findings indicate that miR-26a replacement is a potential therapeutic strategy for metastatic melanoma, and that SODD in particular is a potentially useful therapeutic target.