| Autor: |
Ervolino De Oliveira C; Department of Oral Diagnosis, School of Dentistry, University of Campinas, Piracicaba, SP 13414‑018, Brazil., Dourado MR; Department of Oral Diagnosis, School of Dentistry, University of Campinas, Piracicaba, SP 13414‑018, Brazil., Sawazaki-Calone Í; Department of Oral Pathology and Oral Medicine, Dentistry School, Western Paraná State University, Cascavel, PR 85819‑170, Brazil., Costa De Medeiros M; Departament of Diagnosis and Surgery, School of Dentistry at Araraquara, Araraquara, SP 14801‑385, Brazil., Rossa Júnior C; Departament of Diagnosis and Surgery, School of Dentistry at Araraquara, Araraquara, SP 14801‑385, Brazil., De Karla Cervigne N; Clinical Department, Faculty of Medicine of Jundiai, Jundiai, SP 13202‑550, Brazil., Esquiche León J; Departament of Stomatology, Public Oral Health and Forensic Dentistry, School of Dentistry of Ribeirão Preto, University of São Paulo, Ribeirão Preto, SP 14040‑904, Brazil., Lambert D; Integrated Biosciences, School of Clinical Dentistry and Sheffield Cancer Centre, University of Sheffield, Sheffield S10 2TG, UK., Salo T; Cancer and Translational Medicine Research Unit, Faculty of Medicine and Medical Research Center Oulu, Oulu University Hospital, University of Oulu, Oulu 90220, Finland., Graner E; Department of Oral Diagnosis, School of Dentistry, University of Campinas, Piracicaba, SP 13414‑018, Brazil., Coletta RD; Department of Oral Diagnosis, School of Dentistry, University of Campinas, Piracicaba, SP 13414‑018, Brazil. |
| Abstrakt: |
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 applied in vitro strategies 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 findings 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. |
