Abstract 1104: Nuclear translocalization of DICER correlates with high-risk clinical/histologic features in melanoma

Abstract Melanoma is an aggressive malignancy with a relatively high metastatic rate, responsible for almost 60% of lethal skin tumors. Despite numerous efforts, there is still a need to better understand the molecular pathways involved in malignant melanoma metastasis. In recent years, there have been several studies highlighting the role of deregulated microRNAs (miRNAs) expression in tumor progression and metastasis. DICER is a central regulator of miRNA maturation and recently, has been shown to be upregulated in cutaneous melanoma at both protein and mRNA level. Arur et al. [1], reported DICER to be one of the ERK substrate, and this activation results in its nuclear translocalization (personal communication). However, it is unknown whether differential cellular expression of DICER contributes to the pathogenesis of melanoma. In order to test the hypothesis that aberrant nucleo-cytoplasmic expression of DICER plays a significant role in melanoma progression, we have performed semiquantitative immunohistochemical analysis of DICER in benign nevi (n=17), primary melanomas without metastasis (n=38) and with metastasis (n=27), and melanoma metastases (n=34 cases). A significant positive correlation was observed between the percentage of positive cells (p=0.003) and staining intensity (p=0.01) for nuclear DICER with progression from benign nevi to primary melanoma. Interestingly, primaries without metastasis had significantly higher levels of DICER immunopositivity in tumor cells than primaries with metastasis (p=0.02). Furthermore, metastatic melanomas showed significantly larger number of cells having intense immunoreactivity for DICER protein in nucleus than the primary melanomas (p=0.02). Significantly larger percentage of tumor cells showing DICER expression in the nucleus were observed in those lesions having ulceration (p=0.007) and vertical growth phase, which are well-established markers of poor clinical outcomes in patients with cutaneous melanoma. On the other hand, lesions showing no vascular invasion expressed higher levels of DICER in the cytoplasm (p<0.0001). Disease-specific survival was significantly shorter in patients with increased nuclear expression of DICER (p=0.04). Thus, differential cellular localization of miRNA-regulating DICER protein correlates with disease progression and high-risk clinical and histologic features in melanoma. Therefore, it will be interesting to further delineate the role of nuclear DICER in melanoma. References 1. Arur S, Ohmachi M, Nayak S, et al. Proc Natl Acad Sci U S A. 2009 Mar4;106(12):4776-81. 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 1104. doi:1538-7445.AM2012-1104