Role of SLURP-1 in Melanoma and Melanoma Stem Cells

Melanoma is the most aggressive skin cancer, with a propensity to metastasize, and is resistant to most of the current therapeutic regimens. Incidence rate of melanoma in patients with MDM (Mal De Maleda, with SLURP-1 mutation) is much higher than normal counterpart. SLURP-1 (lymphocyte antigen 6/urokinase-type plasminogen activator receptor related protein-1) is an allosteric agonist to the nicotinic acetylcholine receptor (nAchR) and it regulates epidermal homeostasis and T-cell function. The preliminary results of comparing human peripheral blood mononuclear cells (PBMCs) from 4 affected and 15 unaffected members from the family with MDM revealed that T-cell activation was impaired in PBMCs with the heterozygous and homozygous SLURP-1 G86R mutation. (2 of affected members developed melanoma.) Since there is currently no effective treatment for metastatic melanoma, identifying novel molecular mechanisms may lead to development of new treatments for metastatic melanomas. Previous study showed that melanoma stem cells (MSCs) are crucial in melanoma pathogenesis: 1.Melanoma contains ABCB5, CD133 and ABCG2 positive cells had enhanced tumorigenic potential. 2.Higher frequencies of cells capable of initiating melanoma xenografts when using IL2Rγ-/- NOD SCID mice. These data confirmed the interaction between T cells and MSCs. In this project, we will investigate the roles of SLURP-1 in melanoma and MSCs. Investigating and verifying the interaction between T-cells from patients with MDM and melanoma cells to confirm the SLURP-1 function of tumorigenesis in xenotransplant mice (IL2Rγ-/- NOD SCID) model. To reveal the role of SLURP-1 silencing in melanoma cell lines by using not only A2058 , A375 and MeWo mwlanima cell lines but also ABCB5+ melanoma cells and ABCB5- melanoma cells through the tumorigenesis, apoptosis,angiogenesis, proliferation, melanosphere formation assays. The aim of this project is to investigate the roles and molecular mechanisms of SLURP-1 in melan