Phthalate exposure induces microRNA-5010/Nrf2-EGR1/GDF15 signaling expression in prostate cancer

IF 6.1 2区环境科学与生态学 Q1 ENVIRONMENTAL SCIENCES

Ecotoxicology and Environmental Safety Pub Date : 2025-01-15 DOI:10.1016/j.ecoenv.2025.117759

Yuh-Shyan Tsai , Yeong-Chin Jou , Ian Seng Cheong , Hsiu-Ting Tung , Lin-Nei Hsu , Hsin-Tzu Tsai , Tzong-Shin Tzai

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Abstract

Phthalate exposure is linked to prostate enlargement through sex hormonal changes and oxidative stress. However, its role and action mechanism in prostate cancer remain unclear. This study examined two patient cohorts: 204 patients undergoing prostate biopsy (24 benign and 180 malignancies) and 85 with confirmed prostate cancer receiving robotic-assisted radical prostatectomy. Urine samples, collected with informed consent, were analyzed for urinary DEHP metabolites using HPLC-MS and ELISA. Patients with prostate cancer exhibited significantly higher urinary MEOHP and ΣDEHP metabolite levels than those who underwent benign biopsy (unpaired t-test, p = 0.027 and 0.039, respectively). MIR-5010 upregulation and MIR-205 downregulation were observed in two paired small RNA sequencing analyses (urine pellets of benign vs. malignant patients and PC3 cells without or with DEHP treatment), correlating with tumor staging in the TCGA prostate cancer cohort. Unlike MIR-205, a known tumor suppressor gene in prostate cancer, gene set enrichment analysis revealed that higher MIR-5010 expression was linked to increased Nrf-2 downstream signaling (enriched score: 0.35; p = 0.17). In vitro assays in prostate cancer cells showed that DEHP enhanced Nrf-2 protein expression and its downstream signaling molecules (i.e., SOD2, Heme oxygenase-1, and EGR-1) while increasing GDF15 mRNA expression via EGR-1 regulation in a dose- and time-dependent manner. Furthermore, urinary GDF15 levels were positively associated with urinary MEOHP and MEHP metabolites in the biopsy cohort (p = 0.0007 and 0.011, respectively) and with urinary oxidative stress marker 8-OHdG, aggressive marker VEGF, and CCL2/MCP-1 levels in the prostatectomy cohort (p = 0.0004, 0.006, and 0.0034, respectively). These findings suggest that phthalate exposure induces Nrf-2 and its downstream signaling (i.e., EGR-1/GDF-15) through microRNA regulation, contributing to prostate cancer aggressiveness.

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邻苯二甲酸盐暴露诱导前列腺癌中microRNA-5010/Nrf2-EGR1/GDF15信号的表达。

邻苯二甲酸盐暴露通过性激素变化和氧化应激导致前列腺肿大。然而，其在前列腺癌中的作用和作用机制尚不清楚。本研究检查了两组患者：204例接受前列腺活检的患者（24例良性和180例恶性）和85例确诊前列腺癌接受机器人辅助根治性前列腺切除术的患者。在知情同意的情况下收集尿液样本，使用HPLC-MS和ELISA分析尿液DEHP代谢物。前列腺癌患者尿MEOHP和ΣDEHP代谢物水平明显高于良性活检患者（未配对t检验，p = 0.027和0.039）。在两组配对的小RNA测序分析中（良性与恶性患者的尿球和未经或接受DEHP治疗的PC3细胞），MIR-5010上调和MIR-205下调，与TCGA前列腺癌队列中的肿瘤分期相关。与前列腺癌中已知的肿瘤抑制基因MIR-205不同，基因集富集分析显示，MIR-5010的高表达与Nrf-2下游信号的增加有关(富集评分：0.35； = 0.17页)。前列腺癌细胞体外实验显示，DEHP可增强Nrf-2蛋白及其下游信号分子（SOD2、Heme oxygenase-1、EGR-1）的表达，同时通过EGR-1调控GDF15 mRNA的表达，且呈剂量和时间依赖性。此外，尿GDF15水平与活检组尿MEOHP和MEHP代谢物呈正相关（p = 0.0007和0.011），与前列腺切除术组尿氧化应激标志物8-OHdG、侵袭性标志物VEGF和CCL2/MCP-1水平呈正相关（p = 0.0004、0.006和0.0034）。这些发现表明，邻苯二甲酸盐暴露通过microRNA调控诱导Nrf-2及其下游信号（即EGR-1/GDF-15），从而促进前列腺癌的侵袭性。

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来源期刊

Ecotoxicology and Environmental Safety 环境科学-毒理学

CiteScore

12.10

自引率

5.90%

发文量

1234

审稿时长

88 days

期刊介绍： Ecotoxicology and Environmental Safety is a multi-disciplinary journal that focuses on understanding the exposure and effects of environmental contamination on organisms including human health. The scope of the journal covers three main themes. The topics within these themes, indicated below, include (but are not limited to) the following: Ecotoxicology、Environmental Chemistry、Environmental Safety etc.