Activin A inhibits vascular endothelial cell growth and suppresses tumour angiogenesis in gastric cancer

BACKGROUND: Activin A is a multi-functional cytokine belonging to the transforming growth factor-beta (TGF-beta) superfamily; however, the effect of activin A on angiogenesis remains largely unclear. We found that inhibin beta A subunit (INHBA) mRNA is overexpressed in gastric cancer (GC) specimens and investigated the effect of activin A, a homodimer of INHBA, on angiogenesis in GC. METHODS: Anti-angiogenic effects of activin A via p21 induction were evaluated using human umbilical vein endothelial cells (HUVECs) in vitro and a stable INHBA-introduced GC cell line in vivo. RESULTS: Compared with TGF-beta, activin A potently inhibited the cellular proliferation and tube formation of HUVECs with induction of p21. A promoter assay and a chromatin immunoprecipitation assay revealed that activin A directly regulates p21 transcriptional activity through Smads. Stable p21-knockdown significantly enhanced the cellular proliferation of HUVECs. Notably, stable p21-knockdown exhibited a resistance to activin-mediated growth inhibition in HUVECs, indicating that p21 induction has a key role on activin A-mediated growth inhibition in vascular endothelial cells. Finally, a stable INHBA-introduced GC cell line exhibited a decrease in tumour growth and angiogenesis in vivo. CONCLUSION: Our findings highlight the suppressive role of activin A, unlike TGF-beta, on tumour growth and angiogenesis in GC. British Journal of Cancer (2011) 105, 1210-1217. doi:10.1038/bjc.2011.348 www.bjcancer.com Published online 6 September 2011 (C) 2011 Cancer Research UK