Role of SLURP-1 in Melanoma and Melanoma Stem Cells

Cutaneous melanoma is an aggressive neoplasm refractory to traditional therapies, especially at the metastatic stage. Furthermore, its incidence is continuously increasing during the last decade (1). Melanomas develop through a multistep process that from normal melanocytes proceeds to nevi and to radial and vertical growth phase tumors (2). During this process, melanomas are characterized by certain well-defined genetic alterations as well as frequent chromosomal aberrations associated with tumor progression (3). However, the molecular mechanisms involved in the carcinogenesis and progression of melanoma are complex and not entirely clear (4). Because of the intractability of metastatic melanomas with only 14% of the patients survive for 5 years and no effective treatments (2), understanding the underlying molecular mechanisms involved in melanoma and identifying molecular markers may lead to improvements in therapeutic approaches for metastatic melanomas. Mal de Meleda (MDM; OMIM 248300) is a rare autosomal recessive disorder characterized by erythema and hyperkeratosis of the palms and soles, extending to the dorsal aspects of the hands and feet (known as transgrediens), and perioral erythema and psoriasiform plaques on the elbows and knees. (5-7) Homozygous mutations of the SLURP1 gene (previously known as ARS component B) encoding lymphocyte antigen 6/urokinase-type plasminogen activator receptor related protein-1 (SLURP-1) have been identified as the cause of MDM. (8-10) Mutations of the SLURP1 gene affect the expression, integrity and stability of SLURP-1 on the upper layer of the epidermis and in cultured mature keratinocytes. (11) Other studies also demonstrated that SLURP-1 acts as a positive allosteric ligand for 7-nAchR in keratinocytes, eliciting proapoptotic activity and differentiation. (12,13) As well as in epidermis and keratinocytes, the expression of SLURP-1 has been found in T cells, B cells, dendritic cells and macrophages. (14-15) Malignant melanoma (MM) has been reported to be the predominant cutaneous malignancy occurring in the hyperkeratotic area in patients with MDM. (16) The incidence of MM in MDM is significantly higher than in the general population.(17) At least six cases of MM have been reported in patients with MDM;27-29 two of the reported cases were siblings. (18) The possible explanations of the higher incidence of MM in patients with MDM include: (i) lack of proapoptotic effect of SLURP-1; (ii) defective T-cell activation and tumour monitoring; or (iii) prolonged inflammation in hyperkeratotic skin. The previous study showed that peripheral blood mononuclear cells (PBMCs) with the heterozygous and homozygous SLURP-1 G86R mutation had defective T-cell activation. This was restored by the addition of 0•5 μg mL-1 recombinant human SLURP-1 protein. (19) Previous study showed that a putative monoclonal antibody that recognized ABCB5 was used to isolate melanoma stem cells (MSCs). (20) In this study, the investigators will investigate the roles of SLURP-1 in melanoma cells (including MSC) and also its interaction between melanoma cells and T-cells. Aims： 1. To evaluate the significance and correlation of SLURP-1 expression in melanoma cells and melanoma metastasis in human tissues and mouse metastasis models. 2. To assess the function of the SLURP-1 protein in melanoma cells and melanoma stem cells. 3. To investigate the interaction between T-cells with SLURP-1 mutation and melanoma cells / MSCs. 4. Confirm the biological effects of SLURP-1 on melanoma cells / MSCs. 5. To investigate the relationship between SLURP-1 overexpression and melanoma cancer biology. References 1. Gray-Schopfer V, Wellbrock C, Marais R. Melanoma biology and new target therapy. Nature 2007; 445: 851-7. 2. Miller AJ, Mihm MC. Melanoma. 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