Melanoma is the most lethal form of skin cancer in the United States and the risk of developing melanoma is increasing. The survival rate for melanoma is very high when detected early; however, there is a need for new and more accurate diagnostic tests, as well as innovative therapies. The histopathologic interpretation of cutaneous melanoma coupled with earlier diagnosis remains one the most frustrating and difficult areas in dermatopathology and surgical pathology and therefore, there is an unquestioned need to identify sensitive and specific diagnostic markers. The long-term goal of our research is to improve early detection methods for melanoma, and to help predict the risk that early skin lesions will progress to cancer. The proposed study is significant, as it focuses o a melanocyte specific miRNA, miR-211, and its target genes that may be key regulators for tumorigenesis and can be used as early diagnostic markers for melanoma. Our central hypothesize is that miR-211 is an early indicator of the development of melanoma, and dysregulated expression of miR-211 and its target genes are involved in the progression of melanocytes to melanomas. We plan to test our central hypothesis and accomplish the overall objective of this application by pursing the following experiments. First, we will establish the functional relevance of miR-211 and its new target genes (IGFBP5, NFAT-5, RUNX2, IRF2BP2) which we have identified by Affymetrix array and validated by qRT-PCR. Second, we will mine the existing deep-sequencing (RNA-seq) data from miR-211- expressing melanoma cells (A375/miR-211, and WM1552C/miR-211) to identify additional target and regulatory genes to expand the miR- 211 signaling pathway. Third, we will identify the expression of miR-211 and its target genes in tissue samples (clinical biopsies) from patients with differentially staged melanoma, and in control melanocytic nevi and normal skin. Fourth, we will determine the relevance of miR-211 and its target genes to melanoma staging and development. Finally, the work proposed here is innovative, because it will identify the role of miR-211 and its target genes in melanoma and provide evidence that miR-211 and target genes are early prognostics markers capable of finer classification of this often-fatal disease. The translational impact of ths study will be to improve early melanoma detection, to help predict the risk of melanoma, and to distinguish benign lesion and precancerous lesions.