Epigenetic modulators hydralazine and sodium valproate act synergistically in VEGI-mediated anti-angiogenesis and VEGF interference in human osteosarcoma and vascular endothelial cells
Epigenetic modulators hydralazine and sodium valproate act synergistically in VEGI-mediated anti-angiogenesis and VEGF interference in human osteosarcoma and vascular endothelial cells
复制标题
DOI：
10.3892/ijo.2019.4811
复制
发表时间：
2019-07-01
影响因子：
5.2
通讯作者：
Yoshiya, Shinichi
中科院分区：
文献类型：
--
作者：
Kumanishi, Shunsuke;Yamanegi, Koji;Yoshiya, Shinichi
血管内皮细胞生长抑制因子(VEGI；又称TNFSF15或TL1A)参与调节血管内稳态。已知VEGI通过两种受体发挥作用：死亡受体-3(DR3)和诱骗受体-3(DcR3)。DR3是目前已知的唯一的VEGI功能性受体，它含有一个死亡结构域，可诱导细胞凋亡。DcR3以可溶性蛋白的形式分泌，拮抗VEGI/DR3的相互作用。在一些癌症中已经检测到DcR3的过度表达和VEGI的下调。本研究旨在观察组蛋白脱乙酰酶抑制剂丙戊酸钠(VPA)与DNA甲基化抑制剂盐酸肼(Hy)合用对人骨肉瘤(OS)细胞和人微血管内皮细胞(HMVE)VEGI及其相关受体表达的影响。Hy和VPA联合作用可协同诱导OS和HMVE细胞中VEGI和DR3的表达，而不诱导DcR3的分泌。此外，还观察到VPA和Hy通过VEGI/DR3自分泌和旁分泌途径显著增强对血管形成的抑制作用。此外，免疫沉淀法将VEGI/VEGF-A免疫复合物拉低。综上所述，这些发现表明，DNA甲基转移酶和组蛋白去乙酰化酶抑制剂不仅有可能诱导肿瘤细胞中抑癌基因的重新表达，而且通过增强VEGI/DR3途径和VEGI/VEGF-A干扰而发挥抗血管生成作用。
Vascular endothelial growth inhibitor (VEGI; also referred to as TNFSF15 or TL1A) is involved in the modulation of vascular homeostasis. VEGI is known to operate via two receptors: Death receptor-3 (DR3) and decoy receptor-3 (DcR3). DR3, which is thus far the only known functional receptor for VEGI, contains a death domain and induces cell apoptosis. DcR3 is secreted as a soluble protein and antagonizes VEGI/DR3 interaction. Overexpression of DcR3 and downregulation of VEGI have been detected in a number of cancers. The aim of the present study was to investigate the effects of sodium valproate (VPA), a histone deacetylase inhibitor, in combination with hydralazine hydrochloride (Hy), a DNA methylation inhibitor, on the expression of VEGI and its related receptors in human osteosarcoma (OS) cell lines and human microvascular endothelial (HMVE) cells. Combination treatment with Hy and VPA synergistically induced the expression of VEGI and DR3 in both OS and HMVE cells, without inducing DcR3 secretion. In addition, it was observed that the combination of VPA and Hy significantly enhanced the inhibitory effect on vascular tube formation by VEGI/DR3 autocrine and paracrine pathways. Furthermore, the VEGI/VEGF-A immune complex was pulled down by immunoprecipitation. Taken together, these findings suggest that DNA methyltransferase and histone deacetylase inhibitors not only have the potential to induce the re-expression of tumor suppressor genes in cancer cells, but also exert anti-angiogenic effects, via enhancement of the VEGI/DR3 pathway and VEGI/VEGF-A interference.