ACTIVIN-A DIRECTLY INHIBITS VASCULAR ENDOTHELIAL CELL GROWTH VIA TGF-Β-DEPENDENT SIGNAL PATHWAY

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Abstract

Activin-A is a homodimeric protein consisting of two INHBA (inhibin βA subunit) and belongs to the large transforming growth factor β (TGF-β) superfamily. In cancer, it is known that activin-A is overexpressed in various cancers such as esophageal, pancreatic and ovarian cancers; however, their involvement in angiogenesis remains largely unclear. Our microarray analysis for the clinical specimen of gastric cancer revealed that the mRNA expression of INHBA was overexpressed in gastric cancer cells. To clarify the biological function of activin-A for angiogenesis, we conducted the following experiments. Real-time RT–PCR revealed that INHBA mRNA was overexpressed in several cancer cell lines. Secreted activin-A protein was also confirmed by ELISA and the concentration varied markedly by individual cell lines. Activin-A and TGF-β directly inhibited the cell growth of HUVEC (human umbilical vascular endothelial cells) in a dose-dependent manner. Both activin-A and TGF-β increased the phosphorylation levels of smad on HUVEC cells, suggesting that the TGF-β signal pathway actually functioned in HUVEC cells. Flowcytometry revealed that activin-A and TGF-β induced cell cycle arrest in HUVEC cells. These results suggest that activin-A has a growth inhibitory effect on the vascular endothelial cell and the overexpression of activin-A in gastric cancer may contribute anti-angiogenic roles for tumor growth.

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