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
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
3. To investigate the interaction between T-cells with SLURP-1 mutation and melanoma cells
4. Confirm the biological effects of SLURP-1 on melanoma cells / MSCs.
5. To investigate the relationship between SLURP-1 overexpression and melanoma cancer
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with mal de Meleda. Br J Dermatol. 2010 Sep 21
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melanomas. Nature. 2008 Jan 17;451(7176):345-9
Observational Model: Case Control, Time Perspective: Prospective
Shiou-Hwa Jee, M.D., Ph.D.
Department of Dermatology, National Taiwan University Hospital.
Taiwan: Department of Health