Activin A triggers angiogenesis via regulation of VEGFA and its overexpression is associated with poor prognosis of oral squamous cell carcinoma

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De Oliveira, Carine Ervolino ^{[1, 2]} ; Dourado, Mauricio Rocha ^[1] ; Sawazaki-Calone, Iris ^[3] ; De Medeiros, Marcell Costa ^[4] ; Rossa Junior, Carlos ^[4] ; Cervigne, Nilva De Karla ^[5] ; Leon, Jorge Esquiche ^[6] ; Lambert, Daniel ^{[7, 8]} ; Salo, Tuula ^{[9, 10, 11, 12]} ; Graner, Edgard ^[1] ; Coletta, Ricardo D. ^[1]

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^[1] Univ Estadual Campinas, Sch Dent, Dept Oral Diag, BR-13414018 Piracicaba, SP - Brazil

^[2] Univ Fed Alfenas, Dept Pathol & Parasitol, R Gabriel Monteiro da Silva 700, BR-37130001 Alfenas, MG - Brazil

^[3] Western Parana State Univ, Dent Sch, Dept Oral Pathol & Oral Med, BR-85819170 Cascavel, PR - Brazil

^[4] Sch Dent Araraquara, Dept Diag & Surg, BR-14801385 Araraquara, SP - Brazil

^[5] Fac Med Jundiai, Clin Dept, BR-13202550 Jundiai, SP - Brazil

^[6] Univ Sao Paulo, Sch Dent Ribeirao Preto, Dept Stomatol Publ Oral Hlth & Forens Dent, BR-14040904 Ribeirao Preto, SP - Brazil

^[7] Univ Sheffield, Sch Clin Dent, Integrated Biosci, Sheffield S10 2TG, S Yorkshire - England

^[8] Univ Sheffield, Sheffield Canc Ctr, Sheffield S10 2TG, S Yorkshire - England

^[9] Univ Oulu, Oulu Univ Hosp, Fac Med, Canc & Translat Med Res Unit, Oulu 90220 - Finland

^[10] Univ Oulu, Oulu Univ Hosp, Med Res Ctr Oulu, Oulu 90220 - Finland

^[11] Univ Helsinki, Inst Oral & Maxillofacial Dis, Helsinki 00260 - Finland

^[12] Helsinki Univ Hosp, Dept Pathol, HUSLAB, Helsinki 00260 - Finland

• Tipo de documento: Artigo Científico
• Fonte: International Journal of Oncology; v. 57, n. 1, p. 364-376, JUL 2020.
• Citações Web of Science: 0

Resumo

Poor prognosis associated with the dysregulated expression of activin A in a number of malignancies has been related to with numerous aspects of tumorigenesis, including angiogenesis. The present study investigated the prognostic significance of activin A immunoexpression in blood vessels and cancer cells in a number of oral squamous cell carcinoma (OSCC) cases and appliedin vitrostrategies to determine the impact of activin A on angiogenesis. In a cohort of 95 patients with OSCC, immunoexpression of activin A in both blood vessels and tumor cells was quantified and the association with clinicopathological parameters and survival was analyzed. Effects of activin A on the tube formation, proliferation and migration of human umbilical vein endothelial cells (HUVECs) were evaluated in gain-of-function (treatment with recombinant activin A) or loss-of-function {[}treatment with activin A-antagonist follistatin or by stable transfection with short hairpin RNA (shRNA) targeting activin A] conditions. Conditioned medium from an OSCC cell line with shRNA-mediated depletion of activin A was also tested. The profile of pro- and anti-angiogenic factors regulated by activin A was assessed with a human angiogenesis quantitative PCR (qPCR) array. Vascular endothelial growth factor A (VEGFA) and its major isoforms were evaluated by reverse transcription-qPCR and ELISA. Activin A expression in blood vessels demonstrated an independent prognostic value in the multivariate analysis with a hazard ratio of 2.47 {[}95% confidence interval (CI), 1.30-4.71; P=0.006) for disease-specific survival and 2.09 (95% CI, 1.07-4.08l: P=0.03) for disease-free survival. Activin A significantly increased tubular formation of HUVECs concomitantly with an increase in proliferation. This effect was validated by reduced proliferation and tubular formation of HUVECs following inhibition of activin A by follistatin or shRNA, as well as by treatment of HUVECs with conditioned medium from activin A-depleted OSCC cells. Activin A-knockdown increased the migration of HUVECs. In addition, activin A stimulated the phosphorylation of SMAD2/3 and the expression and production of total VEGFA, significantly enhancing the expression of its pro-angiogenic isoform 121. The present fndings suggest that activin A is a predictor of the prognosis of patients with OSCC, and provide evidence that activin A, in an autocrine and paracrine manner, may contribute to OSCC angiogenesis through differential expression of the isoform 121 of VEGFA. (AU)

• Processo FAPESP: 13/01607-6 - Avaliação do papel biológico das proteínas EEF1D, fascina e plectina em carcinomas espinocelulares orais
• Beneficiário: Ricardo Della Coletta
• Modalidade de apoio: Auxílio à Pesquisa - Regular
• Processo FAPESP: 13/19856-2 - Análise do papel biológico de ativina a na angiogênese em carcinomas espinocelulares orais
• Beneficiário: Carine Ervolino de Oliveira
• Modalidade de apoio: Bolsas no Brasil - Pós-Doutorado