Opposing roles of JNK and p38 in regulating lymphangiogenesis and invasiveness in melanoma

In primary melanoma, the amount of VEGF-C expression and lymphangiogenesis predict 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 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 JNK- and p38/MAPK activities as being responsible for the inverse regulation of VEGF-C and MITF. Predominant JNK signaling results in a VEGF-Clow/MITFhigh phenotype, these melanoma cells are highly proliferative, show low mobility and are poorly lymphangiogenic. Predominant p38 signaling results in a VEGF-Chigh/MITFlow phenotype, corresponding to a slowly cycling, highly mobile, lymphangiogenic and metastatic melanoma. Comparative mRNA expression analysis of a set of 22 human melanoma cell lines