Aberrant expression of miRNAs and their biogenesis factors has been frequently observed in different types of cancer.,We recently reported that expression of DICER1 is reduced in metastatic melanoma.,Nevertheless, so far very little is known about the expression pattern of other miRNA biogenesis factors in this type of malignancy.,Here, we investigated the expression pattern of DROSHA in a large set of melanocytic lesions by tissue microarray and immunohistochemistry (n = 409).,We found that nuclear expression of DROSHA is markedly reduced in the early stages of melanoma progression (P = 0.0001) and is inversely correlated with melanoma thickness (P = 0.0001), AJCC stages (P = 0.0001), and ulceration status (P = 0.002).,We also confirmed the reduced expression of nuclear DROSHA by a second specific antibody raised against a different region of the DROSHA protein.,In addition, we observed that the reduced nuclear expression of DROSHA during melanoma progression is accompanied by an increased cytoplasmic expression of this protein (P = 0.0001).,Finally, we found that expression pattern of DROSHA varies from that of DICER1 and concomitant loss of expression of both DICER1 and DROSHA confers the worse outcome for melanoma patients.,Our results demonstrate a reduced nuclear expression of DROSHA which further highlights a perturbed miRNA biogenesis pathway in melanoma.,In addition, the aberrant subcellular localization of DROSHA indicates possible deregulation in the mechanisms responsible for its proper localization in the nucleus.
MicroRNAs (miRNAs) are small non-coding RNAs (18-24 nucleotides) that have recently been shown to regulate gene expression during cancer progression.,Dicer, a central enzyme in the multi-component miRNA biogenesis pathway, is involved in cutting precursor miRNAs to functionally mature forms.,Emerging evidence shows that Dicer expression is deregulated in some human malignancies and it correlates with tumor progression, yet this role has not yet been investigated in skin cancers.,Using an anti-human monoclonal antibody against Dicer and immunohistochemistry, we compared the expression of Dicer protein among 404 clinically annotated controls and skin tumors consisting of melanocytic nevi (n = 71), a variety of melanomas (n = 223), carcinomas (n = 73) and sarcomas (n = 12).,Results showed a cell-specific up-regulated Dicer in 81% of cutaneous, 80% of acrolentiginous and 96% of metastatic melanoma specimens compared to carcinoma or sarcoma specimens (P<0.0001).,The expression of Dicer was significantly higher in melanomas compared to benign melanocytic nevi (P<0.0001).,In patients with cutaneous melanomas, Dicer up-regulation was found to be significantly associated with an increased tumor mitotic index (P = 0.04), Breslow's depth of invasion (P = 0.03), nodal metastasis (P = 0.04) and a higher American Joint Committee on Caner (AJCC) clinical stage (P = 0.009).,Using western blot analysis, we confirmed the cell-specific up-regulation of Dicer protein in vitro.,A pooled-analysis on mRNA profiling in cutaneous tumors showed up-regulation of Dicer at the RNA level in cutaneous melanoma, also showing deregulation of other enzymes that participate in the biogenesis and maturation of canonical miRNAs.,Increased Dicer expression may be a clinically useful biomarker for patients with cutaneous melanoma.,Understanding deregulation of Dicer and its influence on miRNA maturation is needed to predict the susceptibility of melanoma patients to miRNA-based therapy in the future.