University of Oulu

Ervolino De Oliveira, C., Dourado, M.R., Sawazaki‑Calone, Í., Costa De Medeiros, M., Rossa Júnior, C., De Karla Cervigne, N. ... Coletta, R.D. (2020). Activin A triggers angiogenesis via regulation of VEGFA and its overexpression is associated with poor prognosis of oral squamous cell carcinoma. International Journal of Oncology, 57, 364-376.

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

Saved in:
Author: Ervolino De Oliveira, Carine1,2; Dourado, Maurício Rocha1; Sawazaki‑Calone, Íris3;
Organizations: 1Department of Oral Diagnosis, School of Dentistry, University of Campinas, Piracicaba, SP 13414‑018
2Department of Pathology and Parasitology, Federal University of Alfenas, Alfenas, MG 37130‑001
3Department of Oral Pathology and Oral Medicine, Dentistry School, Western Paraná State University, Cascavel, PR 85819‑170
4Departament of Diagnosis and Surgery, School of Dentistry at Araraquara, Araraquara, SP 14801‑385
5Clinical Department, Faculty of Medicine of Jundiai, Jundiai, SP 13202‑550
6Departament of Stomatology, Public Oral Health and Forensic Dentistry, School of Dentistry of Ribeirão Preto, University of São Paulo, Ribeirão Preto, SP 14040‑904, Brazil
7Integrated Biosciences, School of Clinical Dentistry and Sheffield Cancer Centre, University of Sheffield, Sheffield S10 2TG, UK
8Cancer and Translational Medicine Research Unit, Faculty of Medicine and Medical Research Center Oulu, Oulu University Hospital, University of Oulu, Oulu 90220
9Institute of Oral and Maxillofacial Disease, University of Helsinki, and HUSLAB, Department of Pathology, Helsinki University Hospital, Helsinki 00260, Finland
Format: article
Version: published version
Access: open
Online Access: PDF Full Text (PDF, 1.2 MB)
Persistent link:
Language: English
Published: Spandidos Publications, 2020
Publish Date: 2020-11-04


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.

see all

Series: International journal of oncology
ISSN: 1019-6439
ISSN-E: 1791-2423
ISSN-L: 1019-6439
Volume: 57
Issue: 1
Pages: 364 - 376
DOI: 10.3892/ijo.2020.5058
Type of Publication: A1 Journal article – refereed
Field of Science: 3122 Cancers
Funding: This study was supported by grants from the São Paulo Research Foundation-FAPESP (grant nos. 2013/19856-2 and 2013/01607‑6), and from the National Council for Scientific and Technological Development-CNPq, Brasília, Brazil (grant no. 302964/2015-0).
Copyright information: © Spandidos Publications 2020.