Department of Environmental and Occupational Health, Liaoning Provincial Key Laboratory of Arsenic Biological Effect and Poisoning, School of Public Health, China Medical University, No.77 Puhe Road, Shenyang North New Area, Shenyang 110122, Liaoning Province, People's Republic of China.
Sci Total Environ. 2021 Jan 20;753:141962. doi: 10.1016/j.scitotenv.2020.141962. Epub 2020 Aug 25.
Arsenic (As) is a known human carcinogen with a hitherto unknown mechanism of action. Dimethylarsinic acid (DMA) is a methylated metabolite of arsenicals found in most mammals, and long-term exposure to DMA can lead to bladder cancer in rats. Human epidermal growth factor receptor 2 (HER2) is an oncogenic factor that is overexpressed in bladder cancer, but its role in the initiation and progression of As-induced bladder cancer has not been elucidated. We found that HER2 was up-regulated in human uroepithelial cells treated with arsenite as well as in the bladder tissues of DMA-exposed rats. HER2 overexpression correlated to increased cell proliferation, epithelial-to-mesenchymal transition (EMT), migration and angiogenesis in vitro. The anti-HER2 monoclonal antibody trastuzumab significantly decreased serum vascular endothelial-derived growth factor (VEGF) levels and that of proliferation-related proteins in the bladder tissues of DMA-exposed rats. Furthermore, inhibition of HER2, as well as that of the MAPK, AKT and STAT3 pathways, attenuated arsenite-induced proliferation, migration and angiogenesis of human uroepithelial cells, and increased apoptosis rates in vitro. These findings indicate that HER2 mediates the oncogenic effects of As on bladder epithelial cells by activating the MAPK, PI3K/AKT and Src/STAT3 signaling pathways, and is therefore a promising biomarker.
砷（As）是一种已知的人类致癌物，其作用机制迄今尚不清楚。二甲基砷酸（DMA）是砷化物在大多数哺乳动物中发现的一种甲基化代谢物，长期暴露于 DMA 可导致大鼠膀胱癌。人表皮生长因子受体 2（HER2）是一种致癌因子，在膀胱癌中过度表达，但它在 As 诱导的膀胱癌的发生和发展中的作用尚未阐明。我们发现，亚砷酸盐处理的人尿路上皮细胞以及暴露于 DMA 的大鼠膀胱组织中 HER2 上调。HER2 过表达与体外细胞增殖、上皮-间充质转化（EMT）、迁移和血管生成增加相关。抗 HER2 单克隆抗体曲妥珠单抗显著降低了 DMA 暴露大鼠膀胱组织中的血清血管内皮衍生生长因子（VEGF）水平和增殖相关蛋白的水平。此外，抑制 HER2 以及 MAPK、AKT 和 STAT3 通路，可减弱亚砷酸盐诱导的人尿路上皮细胞增殖、迁移和血管生成，并增加体外细胞凋亡率。这些发现表明，HER2 通过激活 MAPK、PI3K/AKT 和 Src/STAT3 信号通路介导 As 对膀胱上皮细胞的致癌作用，因此是一种很有前途的生物标志物。
