Possible regulation of the immune modulator tetraspanin CD81 by alpha-synuclein in melanoma

Abstract

We probed the mechanism by which the Parkinsons disease-associated protein α–synuclein (α–syn)/SNCApromotes the pathogenesis and progression of melanoma. We found that the human melanoma cell line SK–MEL–28 in whichSNCAis knocked out (SNCA-KO) has low levels of tetraspanin CD81, which is a cell-surface protein that promotes invasion, migration, and immune suppression. Analyzing data from the Cancer Genome Atlas, we show thatSNCAandCD81mRNA levels are positively correlated in melanoma; melanoma survival is inversely related to the levels ofSNCAandCD81; andSNCA/CD81are inversely related to the expression of key cytokine genes (IL12A,IL12B,IFN,IFNG,PRF1andGZMB) for immune activation and immune cell-mediated killing of melanoma cells. We propose that high levels of α–syn and CD81 in melanoma and in immune cells drive invasion and migration and in parallel cause an immunosuppressive microenvironment; these contributing factors lead to aggressive melanomas.