Abstract 3418: Regulation of Dicer expression by Sox4 and its role in melanoma cell invasion and patient survival

Abstract

Abstract Deregulated expression of Sox4 transcription factor has been observed in various types of cancers. We previously reported reduced expression of Sox4 in metastatic melanoma and its role in suppression of cell migration and invasion. We also demonstrated binding of Sox4 to the promoter sequence of Dicer, an RNase involved in maturation of miRNAs. Interestingly, altered expression of Dicer has also been reported in different types of cancers. However, the potential mechanisms which regulate Dicer expression and its potential significance in melanoma are unknown. Here we studied the regulation of Dicer expression by Sox4 and its role in suppression of melanoma invasion. Our data revealed a reduced expression of Dicer mRNA and protein upon Sox4 knockdown. On the other hand, overexpression of Sox4 increased Dicer expression at both mRNA and protein levels. We found that knockdown of Dicer, similar to Sox4 knockdown, enhances the matrigel invasion ability of melanoma cells by at least 2-fold. However, cell growth assays showed that Dicer knockdown does not have a major effect on the growth rate of melanoma cells. In addition, we revealed that overexpression of exogenous Dicer can abrogated the enhanced melanoma cells invasion upon Sox4 knockdown. Furthermore, we examined the expression of Dicer protein in different stages of melanocytic lesions by tissue microarray (TMA) and immunohistochemistry using a construct containing 30 normal nevi, 87 dysplastic nevi, 262 primary and 135 metastatic melanomas. Our data revealed that Dicer expression is inversely correlated with melanoma progression (P<0.0001). Accordingly, the number of samples with positive staining for Dicer reduced from 100% in normal nevi to 85% in dysplastic nevi and 87% in primary melanoma and further reduced to 65% in metastatic melanoma. Expression of Dicer was also negatively correlated with the American Joint Committee on Cancer (AJCC) staging of the melanoma samples (P=0.0004). Strikingly, reduced Dicer expression was correlated with a poorer overall and disease-specific 5-year survival of patients (P=0.015 and 0.0029, respectively). Multivariate Cox regression analysis revealed that reduced Dicer expression is an independent prognostic factor to predict patient outcome (P=0.030). In addition, we analyzed the possible correlation between the expression of Sox4 and Dicer in melanoma TMA samples and found a significant correlation between expression of these markers (P=0.009), further indicating the regulation of Dicer expression by Sox4. Our results pinpoint the regulation of Dicer expression by Sox4 and the critical role of Dicer and probably the miRNA machinery in the suppression of melanoma metastasis. Our data also suggest that Dicer might be a suitable marker for the prognosis of melanoma patients and a potential therapeutic target for human melanoma. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3418. doi:1538-7445.AM2012-3418