Department of Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan Province, PR China.
Department of Hepatobiliary and Pancreatic Surgery/Open and Key Laboratory of Hepatobiliary & Pancreatic Surgery and Digestive Organ Transplantation at Henan Universities/ZhengZhou Key Laboratory of Hepatobiliary & Pancreatic Diseases and Organ Transplantation, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan Province, PR China.
Pharmacol Res. 2021 Jul;169:105648. doi: 10.1016/j.phrs.2021.105648. Epub 2021 May 6.
Phthalates (PAEs) are considered endocrine-disrupting chemicals (EDCs), a series of compounds able to disrupt the normal regulation of the human endocrine-system. In the present study, we investigated the roles of four PAEs, butyl benzyl phthalate (BBP), dibutyl phthalate (DBP), dimethyl phthalate (DMP), and diethyl phthalate (DEP), in hepatocellular carcinoma (HCC) cells. We define novel roles for the PAEs on the migration of HCC cells via their enhancing of the interaction between the pregnane X receptor (PXR) and E26 transformation specific sequence 1 (ETS-1). Our results indicate that PAEs induced the transcriptional activation of ETS-1 and PXR. PXR activated by PAEs could bind to ETS-1 directly and enhanced the activity of ETS-1, which resulted in the induction of invasion-related ETS-1 target genes. The "LXXLL" motif in the ETS-1C-terminal was essential for the interaction between PXR and ETS-1 induced by PAEs. Treatment of PAEs promoted the nuclear accumulation of ETS-1 or the recruitment of ETS-1, but not in cells expressing ETS-1 with a mutated LXXLL motif in its downstream gene promoter region, or following transfection of PXR siRNA. Treatment with the PXR antagonist ketoconazole almost completely inhibited the effects of PAEs. Moreover, PAEs enhanced the in vitro or in vivo invasion of HCC cells via PXR/ETS-1. Therefore, our results not only contribute to a better understanding of HCC, but also extended the roles of EDCs regulating human malignancies.
邻苯二甲酸酯（PAEs）被认为是内分泌干扰化学物质（EDCs），是一系列能够破坏人体内分泌系统正常调节的化合物。在本研究中，我们研究了四种 PAEs，即邻苯二甲酸丁基苄基酯（BBP）、邻苯二甲酸二丁酯（DBP）、邻苯二甲酸二甲酯（DMP）和邻苯二甲酸二乙酯（DEP），在肝癌（HCC）细胞中的作用。我们通过研究发现，PAEs 通过增强妊娠相关 X 受体（PXR）和 E26 转化特异性序列 1（ETS-1）之间的相互作用，对 HCC 细胞的迁移发挥了新的作用。我们的结果表明，PAEs 诱导了 ETS-1 和 PXR 的转录激活。PAEs 激活的 PXR 可以直接与 ETS-1 结合，并增强 ETS-1 的活性，从而诱导侵袭相关的 ETS-1 靶基因的诱导。PAEs 诱导的 PXR 和 ETS-1 之间的相互作用需要 ETS-1 末端的“LXXLL”基序。PAEs 的处理促进了 ETS-1 的核积累或募集，而不是在表达 ETS-1 的细胞中，或者在其下游基因启动子区域中具有突变的“LXXLL”基序的 ETS-1 或在用 PXR siRNA 转染后。用 PXR 拮抗剂酮康唑处理几乎完全抑制了 PAEs 的作用。此外，PAEs 通过 PXR/ETS-1 增强了 HCC 细胞的体外或体内侵袭。因此，我们的研究结果不仅有助于更好地了解 HCC，而且扩展了 EDCs 调节人类恶性肿瘤的作用。
