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J Invest Dermatol. 2016 May;136(5):967-977. doi: 10.1016/j.jid.2016.01.020. Epub 2016 Jan 30.

Opposing Roles of JNK and p38 in Lymphangiogenesis in Melanoma.

Author information

1
Department of Dermatology, Skin and Endothelium Research Division (SERD), Medical University of Vienna, Austria.
2
Department of Vascular Biology and Thrombosis Research, Center for Physiology and Pharmacology, Medical University of Vienna, Austria.
3
Department of Medicine I, Institute of Cancer Research and Comprehensive Cancer Center, Medical University of Vienna, Austria.
4
BBVA Foundation-CNIO Cancer Cell Biology Program, Spanish National Cancer Research Centre (CNIO), Madrid, Spain.
5
Department of Dermatology, Skin and Endothelium Research Division (SERD), Medical University of Vienna, Austria. Electronic address: peter.petzelbauer@meduniwien.ac.at.

Abstract

In primary melanoma, the amount of vascular endothelial growth factor C (VEGF-C) expression and lymphangiogenesis predicts the probability of metastasis to sentinel nodes, but conditions boosting VEGF-C expression in melanoma are poorly characterized. By comparative mRNA expression analysis of a set of 22 human melanoma cell lines, we found a striking negative correlation between VEGF-C and microphthalmia-associated transcription factor (MITF) expression, which was confirmed by data mining in GEO databases of human melanoma Affymetrix arrays. Moreover, in human patients, high VEGF-C and low MITF levels in primary melanoma significantly correlated with the chance of metastasis. Pathway analysis disclosed the respective c-Jun N-terminal kinase and p38/mitogen-activated protein kinase activities as being responsible for the inverse regulation of VEGF-C and MITF. Predominant c-Jun N-terminal kinase signaling results in a VEGF-C(low)/MITF(high) phenotype; these melanoma cells are highly proliferative, show low mobility, and are poorly lymphangiogenic. Predominant p38 signaling results in a VEGF-C(high)/MITF(low) phenotype, corresponding to a slowly cycling, highly mobile, lymphangiogenic, and metastatic melanoma. In conclusion, the relative c-Jun N-terminal kinase and p38 activities determine the biological behavior of melanoma. VEGF-C and MITF levels serve as surrogate markers for the respective c-Jun N-terminal kinase and p38 activities and may be used to predict the risk of metastasis in primary melanoma.

PMID:
26829032
DOI:
10.1016/j.jid.2016.01.020
[Indexed for MEDLINE]
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