General Surgery Center, Department of Hepatobiliary Surgery II, Guangdong Provincial Research Center for Artificial Organ and Tissue Engineering, Guangzhou Clinical Research and Transformation Center for Artificial Liver Institute of Regenerative Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou, China.
Department of Urology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China.
Environ Toxicol. 2022 Oct;37(10):2445-2459. doi: 10.1002/tox.23609. Epub 2022 Jul 1.
Organophosphate flame retardants (OPFRs) have been widely used due to their unique properties. The OPFRs are mainly metabolized in the liver. However, whether the plasma level of OPFRs was involved in the progression of liver cancer remains unclear. Triphenyl phosphate (TPP) is one of the OPFRs that are mostly detected in environment. In this study, we performed CCK8, ATP, and EdU analyses to evaluate the effect of TPP at the concentrations at 0.025-12.8 μM on the proliferation, invasion, and migration of Hep3B, a hepatocellular carcinoma (HCC) cell line. Tumor-bearing mouse model was used for in vivo validation. The results showed that low concentrations of TPP at (0.025-0.1 μM), which are obtained in the plasma of patients with cancers, remarkably promoted cell invasion and migration of Hep3B cells. Animal experiments confirmed that TPP treatment significantly enhanced tumor growth in the xenograft HCC model. To explore the possible molecular mechanisms that might mediate the actions of TPP on Hep3B cells, we profiled gene expression in groups treated with or without TPP at the concentrations of 0.05 and 0.1 μM using transcriptional sequencing. Gene ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment, and Protein-protein interaction (PPI) analyses demonstrated that pathways affected by differentially expressed genes (DEGs) were mainly in nuclear-transcribed mRNA catabolic processes, cytosolic ribosome, and ATPase activity. A 0.05 and 0.1 μM TPP led to up-regulation of a series of genes including EREG, DNPH1, SAMD9, DUSP5, PFN1, CKB, MICAL2, SCUBE3, and CXCL8, but suppressed the expression of MCC. These genes have been shown to be associated with proliferation and movement of cells. Taken together, our findings suggest that low concentration of TPP could fuel the proliferation, invasion, and migration of HCC cells. Thus, TPP is a risk factor in the progression of HCC in human beings.
有机磷阻燃剂（OPFRs）由于其独特的性质而被广泛使用。OPFRs 主要在肝脏中代谢。然而，OPFRs 的血浆水平是否参与肝癌的进展尚不清楚。磷酸三苯酯（TPP）是环境中检测到的 OPFRs 之一。在这项研究中，我们使用 CCK8、ATP 和 EdU 分析来评估浓度在 0.025-12.8μM 之间的 TPP 对 Hep3B（一种肝癌细胞系）增殖、侵袭和迁移的影响，Hep3B 是一种肝癌细胞系。使用荷瘤小鼠模型进行体内验证。结果表明，低浓度的 TPP（0.025-0.1μM），在癌症患者的血浆中可检测到，可显著促进 Hep3B 细胞的侵袭和迁移。动物实验证实，TPP 处理显著增强了异种移植 HCC 模型中的肿瘤生长。为了探索可能介导 TPP 对 Hep3B 细胞作用的分子机制，我们使用转录组测序在 0.05 和 0.1μM 浓度下分别用或不用 TPP 处理的组中对基因表达进行了分析。基因本体（GO）、京都基因与基因组百科全书（KEGG）富集和蛋白质-蛋白质相互作用（PPI）分析表明，受差异表达基因（DEGs）影响的途径主要在核转录 mRNA 分解代谢过程、细胞质核糖体和 ATP 酶活性中。0.05 和 0.1μM TPP 导致一系列基因包括 EREG、DNPH1、SAMD9、DUSP5、PFN1、CKB、MICAL2、SCUBE3 和 CXCL8 的上调，但抑制了 MCC 的表达。这些基因已被证明与细胞的增殖和运动有关。总之，我们的研究结果表明，低浓度的 TPP 可能促进 HCC 细胞的增殖、侵袭和迁移。因此，TPP 是人类 HCC 进展的危险因素。
