Macrophage Inhibitory Cytokine-1 Is Overexpressed in Malignant Melanoma and Is Associated with Tumorigenicity

Abstract

The incidence of malignant melanoma has increased dramatically over the past four decades. Metastatic melanoma is associated with poor prognosis, as the current treatments do not have a significant impact on prolonging survival or decreasing mortality. We have identified a member of the transforming growth factor-beta superfamily, macrophage inhibitory cytokine (MIC)-1, which is highly expressed in melanoma cells. Of 53 melanoma cell lines that were examined for relative MIC-1 expression by western blot analysis, 35 (66%) showed significantly higher levels of MIC-1 compared to normal melanocytes. Primary melanoma biopsies (15 of 22) were found to contain cells expressing low levels of MIC-1 as determined by immunohistochemistry. In contrast, all metastatic melanoma biopsies examined (16 of 16) had strong expression of MIC-1. Expression of MIC-1 was found to be dependent on the mitogen-activated protein kinase pathway, and is a transcriptional target of the microphthalmia-associated transcription factor. Knockdown of MIC-1 expression using stable short-hairpin RNA in three melanoma cell lines showed a significant decrease in tumorigenicity (P<0.0001). These results indicate that MIC-1 may function to promote development of more aggressive melanoma tumors. MIC-1 may be suitable for development as a serum diagnostic and is a possible target for the treatment of metastatic melanoma.