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20 Years
95 Years
Open (Enrolling)

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Trial Information

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.


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
/ 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


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. N Engl J Med 2006; 355: 51-65.

3. Jonsson G, et al. Genomic profiling of malignant melanoma using tiling-resolution array
CGH. Oncogene 2007; 6: 4738-48.

4. Bemis LT, Chen R, Amato CM et al. MicroRNA-137 targets microphthalmia-associated
transcription factor in melanoma cell lines. Cancer Res 2008; 68: 1362-8.

5. Lucker GP, Van De Kerkhof PC, Steijlen PM. The hereditary palmoplantar keratoses: an
updated review and classification. Br J Dermatol 1994; 131:1-14.

6. Bergman R, Bitterman-Deutsch O, Fartasch M et al. Mal de Meleda keratoderma with
pseudoainhum. Br J Dermatol 1993; 128:207-12.

7. Jee SH, Lee YY, Wu YC et al. Report of a family with mal de Meleda in Taiwan: a
clinical, histopathological and immunological study. Dermatologica 1985; 171:30-7.

8. Fischer J, Bouadjar B, Heilig R et al. Mutations in the gene encoding SLURP-1 in Mal de
Meleda. Hum Mol Genet 2001; 10:875-80.

9. Ward KM, Yerebakan O, Yilmaz E et al. Identification of recurrent mutations in the ARS
(component B) gene encoding SLURP-1 in two families with mal de Meleda. J Invest
Dermatol 2003; 120:96-8.

10. Mastrangeli R, Donini S, Kelton CA et al. ARS component B: structural characterization,
tissue expression and regulation of the gene and protein (SLURP-1) associated with mal
de Meleda. Eur J Dermatol 2003; 13:560-70.

11. Favre B, Plantard L, Aeschbach L et al. SLURP1 is a late marker of epidermal
differentiation and is absent in mal de Meleda. J Invest Dermatol 2007; 127:301-8.

12. Grando SA. Basic and clinical aspects of non-neuronal acetylcholine: biological and
clinical significance of non-canonical ligands of epithelial nicotinic acetylcholine
receptors. J Pharmacol Sci 2008; 106:174-9.

13. Arredondo J, Chernyavsky AI, Webber RJ et al. Biological effects of SLURP-1 on human
keratinocytes. J Invest Dermatol 2005; 125:1236-41.

14. Moriwaki Y, Yoshikawa K, Fukuda H et al. Immune system expression of SLURP-1 and
SLURP-2, two endogenous nicotinic acetylcholine receptor ligands. Life Sci 2007;

15. Kawashima K, Yoshikawa K, Fujii YX et al. Expression and function of genes encoding
cholinergic components in murine immune cells. Life Sci 2007; 80:2314-19.

16. Nakajima K, Nakano H, Takiyoshi N et al. Papillon-Lefèvre syndrome and malignant
melanoma. A high incidence of melanoma development in Japanese palmoplantar keratoderma
patients. Dermatology 2008; 217:58-62.

17. Sartore L, Bordignon M, Bassetto F et al. Melanoma in skin affected with keratoderma
palmoplantaris hereditaria (mal de Meleda): treatment with excision and grafting. J Am
Acad Dermatol 2009; 61:161-3.

18. Mozzillo N, Nunziata CA, Caraco C et al. Malignant melanoma developing in an area of
hereditary palmoplantar keratoderma (mal de Meleda). J Surg Oncol 2003; 84:229-33.

19. Tjiu JW, Lin PJ, Wu WH et al. SLURP1 mutation-impaired T-cell activation in a family
with mal de Meleda. Br J Dermatol. 2010 Sep 21

20. Schatton T, Murphy GF, Frank NY et al. Identification of cells initiating human
melanomas. Nature. 2008 Jan 17;451(7176):345-9

Inclusion Criteria:

- Clinical diagnosis of melanoma Disease by NTU hospital(group of cases)

- healthy adults(groups of control)

Exclusion Criteria:

- two groups whose age are younger than 20 or older tha 95 years old

- Clinical diagnosis of non-melanoma Disease by NTU hospital(group of cases)

Type of Study:


Study Design:

Observational Model: Case Control, Time Perspective: Prospective

Principal Investigator

Shiou-Hwa Jee, M.D., Ph.D.

Investigator Role:

Study Chair

Investigator Affiliation:

Department of Dermatology, National Taiwan University Hospital.


Taiwan: Department of Health

Study ID:




Start Date:

January 2011

Completion Date:

July 2019

Related Keywords:

  • Melanoma;
  • healthy adults
  • melanoma
  • Melanoma