Expression of the RNase III enzyme DROSHA is reduced during progression of human cutaneous melanoma

摘要

Aberrant expression of microRNAs (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 (n=409) by tissue microarray and immunohistochemistry. 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.