Department of Biochemistry and Molecular Biology, Nanjing Medical University, Nanjing 211166, China.
Department of Pathology, Xuzhou Medical University, Xuzhou 221004, China.
Int J Mol Sci. 2018 Nov 24;19(12):3739. doi: 10.3390/ijms19123739.
Arsenic trioxide (As₂O₃), a traditional remedy in Chinese medicine, has been used in acute promyelocytic leukemia (APL) research and clinical treatment. Previous studies have shown that As₂O₃ exerts its potent antitumor effects in solid tumors by regulating cell proliferation and survival. The aim of this study was to investigate whether As₂O₃ inhibited gastric cancer cell migration and angiogenesis by regulating FOXO3a expression. We found that As₂O₃ reduced gastric cancer cell viability in a dose-dependent manner and also inhibited cell migration and angiogenesis in vitro. Western blotting and immunofluorescence showed that As₂O₃ downregulated the levels of p-AKT, upregulated FOXO3a expression in the nucleus, and attenuated downstream Vascular endothelial growth factor (VEGF) and Matrix metallopeptidase 9 (MMP9) expression. Moreover, we demonstrated that knockdown of FOXO3a significantly reversed the inhibition of As₂O₃ and promoted cell migration and angiogenesis in vitro. Further, As₂O₃ significantly inhibited xenograft tumor growth and angiogenesis by upregulating FOXO3a expression in vivo. However, knockdown of FOXO3a attenuated the inhibitory effect of As₂O₃ in xenograft tumors, and increased microvessel density (MVD) and VEGF expression. Our results demonstrated that As₂O₃ inhibited migration and angiogenesis of gastric cancer cells by enhancing FOXO3a expression.
三氧化二砷（As₂O₃）是中药中的一种传统药物，已被用于急性早幼粒细胞白血病（APL）的研究和临床治疗。先前的研究表明，As₂O₃通过调节细胞增殖和存活来发挥其在实体瘤中的强大抗肿瘤作用。本研究旨在探讨 As₂O₃是否通过调节 FOXO3a 表达来抑制胃癌细胞迁移和血管生成。我们发现，As₂O₃呈剂量依赖性地降低胃癌细胞活力，并在体外抑制细胞迁移和血管生成。Western blot 和免疫荧光结果显示，As₂O₃下调了 p-AKT 的水平，上调了核内 FOXO3a 的表达，并减弱了下游血管内皮生长因子（VEGF）和基质金属蛋白酶 9（MMP9）的表达。此外，我们证实 FOXO3a 的敲低显著逆转了 As₂O₃的抑制作用，并促进了体外细胞迁移和血管生成。此外，As₂O₃通过上调体内 FOXO3a 的表达，显著抑制了异种移植瘤的生长和血管生成。然而，FOXO3a 的敲低减弱了 As₂O₃在异种移植瘤中的抑制作用，并增加了微血管密度（MVD）和 VEGF 的表达。我们的研究结果表明，As₂O₃通过增强 FOXO3a 的表达来抑制胃癌细胞的迁移和血管生成。
