Department of Medical Microbiology, School of Basic Medical Science, Shandong University, Jinan, Shandong, China.
Department of Hepatology and Gastroenterology, Qilu Hospital of Shandong University, Jinan, Shandong, China.
J Cell Biochem. 2019 Aug;120(8):12665-12676. doi: 10.1002/jcb.28534. Epub 2019 Mar 4.
The mechanism of environmental pollution promoting gastric cancer incidence and difficulty of treatment is not fully understood. In the present article, perfluorodecanoic acid (PFDA), a common persistent environmental pollutant, was used to treat the gastric cell lines and mice to test its genotoxicity. The γ-H2AX immunoblot and plasmid fragment PCR results showed that PFDA had a promotion effect on the DNA double-strand breaks (DSBs) in human and mouse cells. Subsequent results showed that PFDA significantly altered the sensitivity of cells to chemotherapy. Microarray data showed that the expressions of some important DNA repair genes were changed. Further investigation discovered that PFDA inhibition of DNA repair was mediated by X-ray repair cross complementing 4 (XRCC4). The cells deficient in XRCC4 generally exhibited reduced proliferation and premature aging in culture; however, our results indicated that PFDA induced p53 inhibition rescued cells from the apoptosis that was triggered by nonhomologous end-joining (NHEJ) inactivation, and overexpression of p53 expression in PFDA-treated cells enhanced their apoptosis. Finally, T-cell specific factor 4 was suggested by the results as an upstream regulator of XRCC4. This article revealed for the first time that perfluorinated chemicals affect chemotherapeutic sensitivity and the NHEJ pathway, and p53 reduction rescues cells from death.
环境污染促进胃癌发生和治疗困难的机制尚未完全阐明。在本文中，使用全氟癸酸（PFDA），一种常见的持久性环境污染物，处理胃细胞系和小鼠，以测试其遗传毒性。γ-H2AX 免疫印迹和质粒片段 PCR 结果表明，PFDA 对人和小鼠细胞的 DNA 双链断裂（DSB）有促进作用。随后的结果表明，PFDA 显著改变了细胞对化疗的敏感性。微阵列数据显示，一些重要的 DNA 修复基因的表达发生了变化。进一步的研究发现，PFDA 通过 X 射线修复交叉互补蛋白 4（XRCC4）抑制 DNA 修复。XRCC4 缺陷的细胞在培养中通常表现出增殖减少和过早衰老；然而，我们的结果表明，PFDA 诱导的 p53 抑制挽救了因非同源末端连接（NHEJ）失活而引发凋亡的细胞，并且在 PFDA 处理的细胞中过表达 p53 表达增强了它们的凋亡。最后，结果表明 T 细胞特异性因子 4 是 XRCC4 的上游调节因子。本文首次揭示了全氟化学品影响化疗敏感性和 NHEJ 途径，并且 p53 减少挽救了细胞免于死亡。
