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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 melanoma carcinogenesis, which may improve the development of novel treatments for melanoma.
Full description
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.
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150 participants in 2 patient groups
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Shiou-Hwa Jee, M.D., Ph.D.
Data sourced from clinicaltrials.gov
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