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Opposing Roles of JNK and p38 in Lymphangiogenesis in Melanoma
AuthorPetzelbauer, Peter ; Berger, Walter ; Wagner, Erwin F. ; Loewe, Robert ; Schmid, Johannes A. ; Pirker, Christine ; Wenzina, Judith ; Schweighofer, Bernhard ; Friedl, Peter ; Hoesel, Bastian ; Heinz, Magdalena ; Puujalka, Emmi
Published in
Journal of Investigative Dermatology, New York, 2016, Vol. 136, Issue 5, page 967-977
PublishedNew York : Elsevier, 2016
Document typeJournal Article
Keywords (EN)growth-factor-c / suppresses lymph-node / nf-kappa-b / cutaneous melanoma / transcription factor / distant metastases / up-regulation / mitf / expression / cancer
Project-/ReportnumberF 5408-B21
URNurn:nbn:at:at-ubmuw:3-1769 Persistent Identifier (URN)
 The work is publicly available
Opposing Roles of JNK and p38 in Lymphangiogenesis in Melanoma [2.57 mb]
Abstract (English)

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/MITFhigh phenotype; these melanoma cells are highly proliferative, show low mobility, and are poorly lymphangiogenic. Predominant p38 signaling results in a VEGF-C-high/MITFlow 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.

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