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Home / Equine Research Bank / BMC Cancer / Constitutive activation of the ERK pathway in melanoma and s...
BMC cancer2014; 14; 857; doi: 10.1186/1471-2407-14-857

Constitutive activation of the ERK pathway in melanoma and skin melanocytes in Grey horses.

Abstract: Constitutive activation of the ERK pathway, occurring in the vast majority of melanocytic neoplasms, has a pivotal role in melanoma development. Different mechanisms underlie this activation in different tumour settings. The Grey phenotype in horses, caused by a 4.6 kb duplication in intron 6 of Syntaxin 17 (STX17), is associated with a very high incidence of cutaneous melanoma, but the molecular mechanism behind the melanomagenesis remains unknown. Here, we investigated the involvement of the ERK pathway in melanoma development in Grey horses. Methods: Grey horse melanoma tumours, cell lines and normal skin melanocytes were analyzed with help of indirect immunofluorescence and immunoblotting for the expression of phospho-ERK1/2 in comparison to that in non-grey horse and human counterparts. The mutational status of BRAF, RAS, GNAQ, GNA11 and KIT genes in Grey horse melanomas was determined by direct sequencing. The effect of RAS, RAF and PI3K/AKT pathways on the activation of the ERK signaling in Grey horse melanoma cells was investigated with help of specific inhibitors and immunoblotting. Individual roles of RAF and RAS kinases on the ERK activation were examined using si-RNA based approach and immunoblotting. Results: We found that the ERK pathway is constitutively activated in Grey horse melanoma tumours and cell lines in the absence of somatic activating mutations in BRAF, RAS, GNAQ, GNA11 and KIT genes or alterations in the expression of the main components of the pathway. The pathway is mitogenic and is mediated by BRAF, CRAF and KRAS kinases. Importantly, we found high activation of the ERK pathway also in epidermal melanocytes, suggesting a general predisposition to melanomagenesis in these horses. Conclusions: These findings demonstrate that the presence of the intronic 4.6 kb duplication in STX17 is strongly associated with constitutive activation of the ERK pathway in melanocytic cells in Grey horses in the absence of somatic mutations commonly linked to the activation of this pathway during melanomagenesis. These findings are consistent with the universal importance of the ERK pathway in melanomagenesis and may have valuable implications for human melanoma research.
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Publication Date: 2014-11-21 PubMed ID: 25413220PubMed Central: PMC4254013DOI: 10.1186/1471-2407-14-857Google Scholar: Lookup
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  • Journal Article
  • Research Support
  • Non-U.S. Gov't

Summary

This research summary has been generated with artificial intelligence and may contain errors and omissions. Refer to the original study to confirm details provided. Submit correction.

This research explores why Grey horses, who have a specific genetic mutation in Syntaxin 17 (STX17), have a high incidence of skin melanoma. The study finds that the ERK pathway, commonly associated with melanoma development, is constitutively activated in these horses. Notably, this happens in the absence of other common melanoma-associated genetic mutations, indicating a universal role of the ERK pathway in melanoma development.

Research Methodology

  • This research primarily involved detailed investigations of melanoma tumors, cell lines, and normal skin melanocytes of Grey horses.
  • Techniques such as indirect immunofluorescence and immunoblotting were used to analyze the expression of phospho-ERK1/2 in comparison with non-grey horses and human samples.
  • Mutation status of genes like BRAF, RAS, GNAQ, GNA11 and KIT associated with melanomas were checked through direct sequencing.
  • Further, the impact of RAS, RAF, and PI3K/AKT pathways on the activation of the ERK signaling in Grey horse melanoma cells was investigated using specific inhibitors and immunoblotting.
  • Lastly, individual roles of RAF and RAS kinases on the ERK activation were analyzed using si-RNA based approach and immunoblotting.

Research Findings

  • The ERK pathway was found to be constitutively activated in Grey horse melanoma tumours and cell lines, even without common somatic mutations in BRAF, RAS, GNAQ, GNA11, and KIT genes or alteration of main pathway components.
  • This pathway was found to be mitogenic and is mediated by BRAF, CRAF, and KRAS kinases.
  • Notably, higher activation of the ERK pathway was also found in epidermal melanocytes, indicating a general predisposition to melanoma in these horses.

Conclusions

  • The study concludes that presence of the intronic 4.6 kb duplication in STX17 gene is strongly linked with constitutive activation of the ERK pathway in Grey horses, even in absence of typically observed somatic mutations linked to melanoma.
  • This suggests the universal importance of the ERK pathway in melanoma development and brings valuable insights for human melanoma research.

Cite This Article

APA
Jiang L, Campagne C, Sundström E, Sousa P, Imran S, Seltenhammer M, Pielberg G, Olsson MJ, Egidy G, Andersson L, Golovko A. (2014). Constitutive activation of the ERK pathway in melanoma and skin melanocytes in Grey horses. BMC Cancer, 14, 857. https://doi.org/10.1186/1471-2407-14-857

Publication

BMC cancer
ISSN: 1471-2407
NlmUniqueID: 100967800
Country: England
Language: English
Volume: 14
Pages: 857

Researcher Affiliations

Jiang, Lin
    Campagne, Cécile
      Sundström, Elisabeth
        Sousa, Pedro
          Imran, Saima
            Seltenhammer, Monika
              Pielberg, Gerli
                Olsson, Mats J
                  Egidy, Giorgia
                    Andersson, Leif
                      Golovko, Anna
                      • Science for Life Laboratory, Department of Medical Biochemistry and Microbiology, Uppsala University, Box 582, SE-751 23 Uppsala, Sweden. Anna.Golovko@imbim.uu.se.

                      MeSH Terms

                      • Animals
                      • Cell Line, Tumor
                      • Genetic Variation
                      • Genotype
                      • Horse Diseases / genetics
                      • Horse Diseases / metabolism
                      • Horses
                      • Humans
                      • MAP Kinase Signaling System
                      • Melanocytes / metabolism
                      • Melanoma / veterinary
                      • Mitogen-Activated Protein Kinase 1 / metabolism
                      • Mitogen-Activated Protein Kinase 3 / metabolism
                      • Oncogene Proteins / genetics
                      • Proto-Oncogene Proteins B-raf / genetics
                      • Proto-Oncogene Proteins p21(ras) / genetics

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