Department of Genome Biology, Kinki University School of Medicine, 377-2 Ohno-higashi, Osaka-Sayama, Osaka 589-8511, Japan.
Br J Cancer. 2011 Oct 11;105(8):1210-7. doi: 10.1038/bjc.2011.348. Epub 2011 Sep 6.
Activin A is a multi-functional cytokine belonging to the transforming growth factor-β (TGF-β) superfamily; however, the effect of activin A on angiogenesis remains largely unclear. We found that inhibin β 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.
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.
Compared with TGF-β, 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.
Our findings highlight the suppressive role of activin A, unlike TGF-β, on tumour growth and angiogenesis in GC.
激活素 A 是一种多功能细胞因子，属于转化生长因子-β（TGF-β）超家族；然而，激活素 A 对血管生成的影响在很大程度上仍不清楚。我们发现，抑制素βA 亚基（INHBA）mRNA 在胃癌（GC）标本中过度表达，并研究了激活素 A（INHBA 的同源二聚体）对 GC 中血管生成的影响。
通过体外人脐静脉内皮细胞（HUVEC）和体内稳定引入 INHBA 的 GC 细胞系评估激活素 A 通过诱导 p21 对血管生成的抗血管生成作用。
与 TGF-β相比，激活素 A 强烈抑制 HUVEC 的细胞增殖和管形成，并诱导 p21。启动子测定和染色质免疫沉淀测定显示，激活素 A 通过 Smads 直接调节 p21 的转录活性。稳定的 p21 敲低显着增强了 HUVEC 的细胞增殖。值得注意的是，稳定的 p21 敲低在 HUVEC 中表现出对激活素介导的生长抑制的抗性，表明 p21 诱导在血管内皮细胞中对激活素 A 介导的生长抑制起关键作用。最后，稳定引入 INHBA 的 GC 细胞系在体内表现出肿瘤生长和血管生成减少。
我们的研究结果强调了激活素 A 不同于 TGF-β在 GC 中对肿瘤生长和血管生成的抑制作用。
