Opposing Roles of JNK and p38 in Lymphangiogenesis in Melanoma

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


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.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Analysis of Variance
  • Animals
  • Biomarkers, Tumor / metabolism
  • Blotting, Western
  • Cell Proliferation
  • Disease Models, Animal
  • Enzyme-Linked Immunosorbent Assay
  • Female
  • Humans
  • JNK Mitogen-Activated Protein Kinases / metabolism*
  • Lymphangiogenesis / physiology*
  • Male
  • Melanoma / metabolism
  • Melanoma / pathology*
  • Mice
  • Mice, Hairless
  • Microarray Analysis
  • Real-Time Polymerase Chain Reaction / methods
  • Signal Transduction
  • Skin Neoplasms / metabolism
  • Skin Neoplasms / pathology*
  • Statistics, Nonparametric
  • Tumor Cells, Cultured
  • Vascular Endothelial Growth Factor C / metabolism*
  • Xenograft Model Antitumor Assays
  • p38 Mitogen-Activated Protein Kinases / metabolism*


  • Biomarkers, Tumor
  • Vascular Endothelial Growth Factor C
  • JNK Mitogen-Activated Protein Kinases
  • p38 Mitogen-Activated Protein Kinases