Gene expression and promoter methylation of angiogenic and lymphangiogenic factors as prognostic markers in melanoma

Autor(es):Mostrar menos -

Monteiro, Ana Carolina ^{[1, 2]} ; Muenzner, Julienne K. ^[2] ; Andrade, Fernando ^[3] ; Rius, Flavia Eichemberger ^[1] ; Ostalecki, Christian ^[4] ; Geppert, Carol I. ^[5] ; Agaimy, Abbas ^[5] ; Hartmann, Arndt ^[5] ; Fujita, Andre ^[3] ; Schneider-Stock, Regine ^[2] ; Jasiulionis, Miriam Galvonas ^[1]

Afiliação do(s) autor(es)

^[1] Univ Fed Sao Paulo, Escola Paulista Med, Dept Pharmacol, Sao Paulo - Brazil

^[2] Friedrich Alexander Univ Erlangen Nurnberg FAU, Inst Pathol, Dept Expt Tumor Pathol, Erlangen - Germany

^[3] Univ Sao Paulo, Inst Math & Stat, Dept Comp Sci, Sao Paulo - Brazil

^[4] Friedrich Alexander Univ Erlangen Nurnberg FAU, Univ Klinikum Erlangen, Dept Dermatol, Erlangen - Germany

^[5] Friedrich Alexander Univ Erlangen Nurnberg FAU, Inst Pathol, Erlangen - Germany

• Tipo de documento: Artigo Científico
• Fonte: MOLECULAR ONCOLOGY; v. 13, n. 6, p. 1433-1449, JUN 2019.
• Citações Web of Science: 0

Resumo

The high mortality rate of melanoma is broadly associated with its metastatic potential. Tumor cell dissemination is strictly dependent on vascularization; therefore, angiogenesis and lymphangiogenesis play an essential role in metastasis. Hence, a better understanding of the players of tumor vascularization and establishing them as new molecular biomarkers might help to overcome the poor prognosis of melanoma patients. Here, we further characterized a linear murine model of melanoma progression and showed that the aggressiveness of melanoma cells is closely associated with high expression of angiogenic factors, such as Vegfc, Angpt2, and Six1, and that blockade of the vascular endothelial growth factor pathway by the inhibitor axitinib abrogates their tumorigenic potential in vitro and in the in vivo chicken chorioallantoic membrane assay. Furthermore, analysis of The Cancer Genome Atlas data revealed that the expression of the angiogenic factor ANGPT2 (P-value = 0.044) and the lymphangiogenic receptor VEGFR-3 (P-value = 0.002) were independent prognostic factors of overall survival in melanoma patients. Enhanced reduced representation bisulfite sequencing-based methylome profiling revealed for the first time a link between abnormal VEGFC, ANGPT2, and SIX1 gene expression and promoter hypomethylation in melanoma cells. In patients, VEGFC (P-value = 0.031), ANGPT2 (P-value < 0.001), and SIX1 (P-value = 0.009) promoter hypomethylation were independent prognostic factors of shorter overall survival. Hence, our data suggest that these angio- and lymphangiogenesis factors are potential biomarkers of melanoma prognosis. Moreover, these findings strongly support the applicability of our melanoma progression model to unravel new biomarkers for this aggressive human disease. (AU)

• Processo FAPESP: 16/09179-1 - Função do miRNA-298 no desenvolvimento do melanoma metastático
• Beneficiário: Ana Carolina Monteiro
• Linha de fomento: Bolsas no Exterior - Estágio de Pesquisa - Doutorado
• Processo FAPESP: 13/04829-0 - MicroRNAs associados ao fenótipo metastático do melanoma
• Beneficiário: Ana Carolina Monteiro
• Linha de fomento: Bolsas no Brasil - Doutorado
• Processo FAPESP: 14/13663-0 - Integração de dados de expressão de genes e microRNAs, metiloma e hidroximetiloma de diferentes etapas da progressão do melanoma.
• Beneficiário: Miriam Galvonas Jasiulionis
• Linha de fomento: Auxílio à Pesquisa - Regular
• Processo FAPESP: 17/50122-6 - Multiplex tissue analysis of the tumor microenvironment and crucial factors in melanoma pathogenesis
• Beneficiário: Miriam Galvonas Jasiulionis
• Linha de fomento: Auxílio à Pesquisa - Regular