In this study, however, even in the acral lentiginous melanomas PI3K inhibition showing the highest proportional number of cases of cyclin D1 increase in relation to ROC1 (40%), ROC1/cyclin D1 was not associated with melanoma histological type or Breslow thickness. This shows that ROC1 expression alteration may be an event of melanoma oncogenesis not related to histological type. Even

if a correlation of ROC1/cyclin D1 relationship with Breslow thickness does not occur, the large number of cases with ROC1 expression higher than that of cyclin D1 among melanomas <2 mm in thickness may show a stage during which the host response is still effective in restraining tumor progression. Of the 20 melanoma cases with proportional ROC1 and cyclin D1 expressions (32.3%), amplification of the CCND1 gene was seen in only two. In the melanocytic nevus group, both proteins were proportionally expressed in six cases (10.3%), and none of them showed gene amplification. In the non-amplified melanocytic nevi

with proportional ROC1/cyclin Alectinib solubility dmso D1, cyclin D1 was expressed in <25% of cells and in most cases. On the other hand, in the melanoma group, only five cases showed cyclin D1 in <25% of cells, while six cases exhibited cyclin D1 expression in >50% of cells associated with ROC1 expression also in >50% of the cells. This finding suggests that, despite a ROC1 expression decrease in some cases, cyclin D1 levels in melanocytic nevi remained unchanged possibly due to a predominating cyclin D1 gene expression control mechanism. In melanomas, Glutathione peroxidase the mechanism regulating cyclin D1 expression may be something other than gene expression increase and ubiquitination failure. It might include the deficiency of other proteins involved in cyclin

ubiquitination, such as cullins proteins. In most melanocytic nevi, ROC1 protein was expressed by >75% of cells. Deficient ROC1 expression was associated with skin melanomas, where ROC1 expression negatively correlated with cyclin D1 expression, demonstrating the leading role of ROC1 in cyclin D1 degradation within these tumors. The ROC1/cyclin D1 expression relationship correlated with neoplasia type. In melanocytic nevi, there was a predominance of increased ROC1 in relation to cyclin D1 expression, whereas in the melanoma group, about one fourth of the cases showed increased cyclin D1 as compared to ROC1 expression. Neither ROC1 levels nor the ROC1/cyclin D1 expression relationship correlated with Breslow thickness or melanoma histological type. However, studies including a larger number of cases with 1.01–2-mm-thick melanomas and acral lentiginous melanomas are necessary to determine whether these parameters actually correlate.