活性邻苯二甲酸酯代谢物DHEP通过上调β-连环蛋白和下调KLF7诱导前列腺癌细胞的增殖和转移。
The active phthalate metabolite, DHEP, induces proliferation and metastasis of prostate cancer cells via upregulation of β-catenin and downregulation of KLF7.
发表日期：2023 Sep 15
作者：
Hecheng Li, Jianping Li, Yubo Ma, Ziming Wang, Zihe Peng, Hang Xu, Hang Bi, Shaik Althaf Hussain, Zhaolun Li
来源：
BIOORGANIC CHEMISTRY
摘要：
邻苯二甲酸酯(如DHEP)是工业中广泛使用的化合物之一。研究表明，DHEP可以在哺乳动物细胞中引起多种生物学效应，其中重点强调了DHEP的致癌效应。本研究旨在通过体外和体内模型评估DHEP暴露对DU145前列腺癌细胞增殖和浸润能力的影响。DU145细胞被处理以逐渐增加的DHEP浓度，并分析肿瘤原性参数。KLF7作为DHEP效应的可能中介物，在DU145中进行了过表达或沉默来评估KLF7对DHEP生物学效应的可能影响。DHEP的影响还在DU145移植瘤模型中进行了研究。适度剂量的DHEP增加了DU145细胞的增殖和迁移。在基因表达模式方面，DHEP降低了p53和KLF7的水平，同时增加了β-连环蛋白的表达。KLF7的沉默在某种程度上传递了与DHEP相似的效应，并增加了DU145细胞的增殖，而KLF7的转导增加了p53和p21的表达，并控制了肿瘤大小。本研究证明了DHEP增加DU145细胞的肿瘤原性特性，并着重关注潜在机制。长期接触DHEP可能导致癌基因和抑癌基因之间平衡的紊乱，这是恶性转化的标志。因此，在安全利用邻苯二甲酸酯的过程中需要特别考虑这一点。版权所有 © 2023 Elsevier Inc. 保留所有权利。
Phthalates such as DHEP are among the widely used compounds in industry. It has been shown that DHEP can convey various biological consequences in mammalian cells, among them, the carcinogenic effects of DHEP are emphasized. The present study aimed to assess the impact of DHEP exposure on the proliferation and invasiveness of DU145 prostate cancer cells through in vitro and in vivo models. The DU145 cells were treated with increasing concentrations of DHEP and the tumorigenic parameters were analyzed. KLF7 as a probable mediator of the effect of DHEP was either overexpressed or knocked down in DU145 to evaluate the probable impact of KLF7 on the biological effects of DHEP. The effect of DHEP was also studied in a DU145 xenograft tumor model. The moderate doses of DHEP increased the proliferation and migration of DU145 cells. In the case of gene expression patterns, DHEP reduced the levels of p53 and KLF7 while elevated the expression of β-catenin. The knock-down of KLF7 conveyed comparable effects to that of DHEP to some degree and increased the proliferation of DU145 cells, while the transduction of KLF7 increased the expressions of p53 and p21 along with controlling the tumor size. The present study demonstrated the potential of DHEP in increasing the tumorigenic properties of DU145 cells along with a focus on the underlying mechanisms. Sustained exposure to DHEP can cause a dysregulation in balance between oncogenes and tumor suppressor genes which is the hallmark of malignant transformation. Thus, special considerations seem necessary for the safe exploitation of phthalates.Copyright © 2023 Elsevier Inc. All rights reserved.