Department of Child, Adolescent Health and Maternal Health, School of Public Health, Capital Medical University, Beijing 100069, China.
Department of Public Health, College of Medicine, Shihezi University, Shihezi 832000, Xinjiang China.
Chem Res Toxicol. 2020 Jun 15;33(6):1458-1467. doi: 10.1021/acs.chemrestox.0c00019. Epub 2020 May 6.
We aimed to systematically evaluate the regulatory effect of arsenic on wnt/β-catenin signaling pathway and to provide theoretical basis for revealing the mechanism of the relationship between arsenic and cell proliferation. The meta-analysis was carried out using Revman5.2 and Stata13.0 to describe the differences between groups with standard mean difference. We found in normal cells that the levels of wnt3a, β-catenin, glycogen synthase kinase-3β phosphorylated at serine 9 (p-GSK-3β(Ser9)), cyclinD1, proto-oncogene c-myc, and vascular endothelial growth factor (VEGF) in the arsenic intervention group were higher than those in the control group, and the level of glycogen synthase kinase-3β (GSK-3β) was lower than that in the control group ( < 0.05, respectively). Subgroup analysis showed that for a long time period (>24 h), the level of β-catenin in the arsenic intervention group was higher than that in the control group, and the level of GSK-3β of the same long-time period (>24 h) with low-dose (≤5 μM) intervention was lower than those in the control group ( < 0.05, respectively). In cancer cells, the levels of β-catenin, cyclinD1, c-myc, and VEGF in the arsenic intervention group were lower than those in the control group, while the level of GSK-3β in the arsenic intervention group was higher than that in the control group ( < 0.05, respectively). Subgroup analysis showed that the levels of β-catenin, cyclinD1, and c-myc in the high-dose (>5 μM) arsenic intervention group were lower than those in the control group, and the levels of β-catenin and cyclinD1 in the high-dose (>5 μM) arsenic intervention group were lower than those in the low-dose (≤5 μM) arsenic intervention group ( < 0.05, respectively). In addition, the regulation of arsenic on β-catenin was dose-dependent in the range of arsenic concentration from 0 to 7.5 μM. This study revealed that arsenic could upregulate wnt/β-catenin signaling pathway in normal cells and downregulate it in cancer cells, and its effect was affected by time and dose.
我们旨在系统评估砷对 wnt/β-连环蛋白信号通路的调节作用，为揭示砷与细胞增殖关系的机制提供理论依据。采用 Revman5.2 和 Stata13.0 进行荟萃分析，用标准均数差描述组间差异。我们发现，在正常细胞中，砷干预组的 wnt3a、β-连环蛋白、丝氨酸 9 磷酸化糖原合酶激酶-3β（p-GSK-3β(Ser9)）、细胞周期蛋白 D1、原癌基因 c-myc 和血管内皮生长因子（VEGF）水平高于对照组，而糖原合酶激酶-3β（GSK-3β）水平低于对照组（均<0.05）。亚组分析表明，对于较长时间（>24 h），砷干预组的β-连环蛋白水平高于对照组，相同长时间（>24 h）低剂量（≤5 μM）干预的 GSK-3β水平低于对照组（均<0.05）。在癌细胞中，砷干预组的β-连环蛋白、细胞周期蛋白 D1、c-myc 和 VEGF 水平低于对照组，而砷干预组的 GSK-3β水平高于对照组（均<0.05）。亚组分析表明，高剂量（>5 μM）砷干预组的β-连环蛋白、细胞周期蛋白 D1 和 c-myc 水平低于对照组，高剂量（>5 μM）砷干预组的β-连环蛋白和细胞周期蛋白 D1 水平低于低剂量（≤5 μM）砷干预组（均<0.05）。此外，在砷浓度为 0 至 7.5 μM 的范围内，砷对β-连环蛋白的调节呈剂量依赖性。本研究表明，砷可上调正常细胞中的 wnt/β-连环蛋白信号通路，下调癌细胞中的该信号通路，其作用受时间和剂量的影响。
