Chou Wei-Chun, Lee Pei-Hsuan, Tan Yan-Yan, Lin Ho-Chen, Yang Chung-Wei, Chen Kuan-Hsueh, Chuang Chun-Yu
Department of Biomedical Engineering and Environmental Sciences, National Tsing Hua University, Hsinchu, Taiwan; National Institute of Environmental Health Sciences, National Health Research Institute, Miaoli, Taiwan.
Department of Biomedical Engineering and Environmental Sciences, National Tsing Hua University, Hsinchu, Taiwan.
Toxicol In Vitro. 2017 Jun;41:133-142. doi: 10.1016/j.tiv.2017.02.012. Epub 2017 Feb 24.
Bisphenol A (BPA) are commonly used in the manufacture of polycarbonate plastics. Higher BPA exposure levels have been found in patients with endometrial hyperplasia that is one of risk factors of endometrial cancer (EC). Aberrant microRNAs (miRNAs) regulation has been observed in the development of cancer. Thus, this study investigated whether BPA exposure can disrupt miRNA regulation and its gene expression regarding to EC carcinogenic progress. Microarray experiments of miRNA and mRNA were performed in human endometrial cancer RL95-2 cells with treatment of low-to-moderate (10, 10 and 10nM) BPA to explore the aberrant genes corresponding to human EC progression. According to the analysis of KEGG pathway and Cytoscape gene network, this study identified that BPA exposure reduced miR-149 expression to down-regulate DNA repair gene ARF6 (ADP-ribosylation factor 6) and tumor protein p53 (TP53), and up-regulate CCNE2 (cyclin E2) potentially to interrupt cell cycle. BPA also increased miR-107 to suppress hedgehog signaling factors, suppressor of fused homolog (SUFU) and GLI family zinc finger 3 (GLI3) to activate hedgehog signaling for cell proliferation underlying carcinogenesis. Furthermore, the BPA-induced cell proliferation was attenuated by transfection with miR-149 mimic and miR-107 inhibitor. These findings provided an insight into potential epigenetic mechanism of BPA exposure on the risk of endometrial carcinogenesis.
双酚A（BPA）常用于制造聚碳酸酯塑料。在子宫内膜增生患者中发现了较高的BPA暴露水平，而子宫内膜增生是子宫内膜癌（EC）的危险因素之一。在癌症发展过程中观察到了异常的微小RNA（miRNA）调控。因此，本研究调查了BPA暴露是否会破坏与EC致癌进程相关的miRNA调控及其基因表达。对人子宫内膜癌RL95-2细胞进行低至中度（10、10和10nM）BPA处理后的miRNA和mRNA微阵列实验，以探索与人类EC进展相对应的异常基因。根据KEGG通路和Cytoscape基因网络分析，本研究发现BPA暴露降低了miR-149的表达，从而下调了DNA修复基因ARF6（ADP核糖基化因子6）和肿瘤蛋白p53（TP53），并可能上调CCNE2（细胞周期蛋白E2）以中断细胞周期。BPA还增加了miR-107以抑制刺猬信号因子、融合抑制同源物（SUFU）和GLI家族锌指3（GLI3），从而激活刺猬信号促进致癌过程中的细胞增殖。此外，用miR-149模拟物和miR-107抑制剂转染可减弱BPA诱导的细胞增殖。这些发现为BPA暴露增加子宫内膜癌风险的潜在表观遗传机制提供了见解。
