title: Opposing Roles of JNK and p38 in Lymphangiogenesis in Melanoma.
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.
authors.affiliation: Department of Dermatology, Skin and Endothelium Research Division (SERD), Medical University of Vienna, Austria.
authors.forename: Emmi
authors.initials: E
authors.lastname: Puujalka
authors.affiliation: Department of Dermatology, Skin and Endothelium Research Division (SERD), Medical University of Vienna, Austria.
authors.forename: Magdalena
authors.initials: M
authors.lastname: Heinz
authors.affiliation: Department of Vascular Biology and Thrombosis Research, Center for Physiology and Pharmacology, Medical University of Vienna, Austria.
authors.forename: Bastian
authors.initials: B
authors.lastname: Hoesel
authors.affiliation: Department of Dermatology, Skin and Endothelium Research Division (SERD), Medical University of Vienna, Austria.
authors.forename: Peter
authors.initials: P
authors.lastname: Friedl
authors.affiliation: Department of Dermatology, Skin and Endothelium Research Division (SERD), Medical University of Vienna, Austria.
authors.forename: Bernhard
authors.initials: B
authors.lastname: Schweighofer
authors.affiliation: Department of Dermatology, Skin and Endothelium Research Division (SERD), Medical University of Vienna, Austria.
authors.forename: Judith
authors.initials: J
authors.lastname: Wenzina
authors.affiliation: Department of Medicine I, Institute of Cancer Research and Comprehensive Cancer Center, Medical University of Vienna, Austria.
authors.forename: Christine
authors.initials: C
authors.lastname: Pirker
authors.affiliation: Department of Vascular Biology and Thrombosis Research, Center for Physiology and Pharmacology, Medical University of Vienna, Austria.
authors.forename: Johannes A
authors.initials: JA
authors.lastname: Schmid
authors.affiliation: Department of Dermatology, Skin and Endothelium Research Division (SERD), Medical University of Vienna, Austria.
authors.forename: Robert
authors.initials: R
authors.lastname: Loewe
authors.affiliation: BBVA Foundation-CNIO Cancer Cell Biology Program, Spanish National Cancer Research Centre (CNIO), Madrid, Spain.
authors.forename: Erwin F
authors.initials: EF
authors.lastname: Wagner
authors.affiliation: Department of Medicine I, Institute of Cancer Research and Comprehensive Cancer Center, Medical University of Vienna, Austria.
authors.forename: Walter
authors.initials: W
authors.lastname: Berger
authors.affiliation: Department of Dermatology, Skin and Endothelium Research Division (SERD), Medical University of Vienna, Austria. Electronic address: peter.petzelbauer@meduniwien.ac.at.
authors.forename: Peter
authors.initials: P
authors.lastname: Petzelbauer
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D014408:Biomarkers, Tumor / Q000378:metabolism; D015153:Blotting, Western; D049109:Cell Proliferation; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism*; D042583:Lymphangiogenesis / Q000502:physiology*; D008297:Male; D008545:Melanoma / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D008812:Mice, Hairless; D046228:Microarray Analysis; D060888:Real-Time Polymerase Chain Reaction / Q000379:methods; D015398:Signal Transduction; D012878:Skin Neoplasms / Q000378:metabolism / Q000473:pathology*; D018709:Statistics, Nonparametric; D014407:Tumor Cells, Cultured; D042582:Vascular Endothelial Growth Factor C / Q000378:metabolism*; D023041:Xenograft Model Antitumor Assays; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
chemical_list: D014408:Biomarkers, Tumor; D042582:Vascular Endothelial Growth Factor C; D048031:JNK Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases