Phthalate exposure induces microRNA-5010/Nrf2-EGR1/GDF15 signaling expression in prostate cancer
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 w...
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| Format: | Article |
| Language: | English |
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Elsevier
2025-01-01
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| Series: | Ecotoxicology and Environmental Safety |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S0147651325000958 |
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| author | Yuh-Shyan Tsai Yeong-Chin Jou Ian Seng Cheong Hsiu-Ting Tung Lin-Nei Hsu Hsin-Tzu Tsai Tzong-Shin Tzai |
| author_facet | Yuh-Shyan Tsai Yeong-Chin Jou Ian Seng Cheong Hsiu-Ting Tung Lin-Nei Hsu Hsin-Tzu Tsai Tzong-Shin Tzai |
| author_sort | Yuh-Shyan Tsai |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-70dfece00aab4903b835cd9d7b3c10ac |
| institution | Kabale University |
| issn | 0147-6513 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Ecotoxicology and Environmental Safety |
| spelling | doaj-art-70dfece00aab4903b835cd9d7b3c10ac2025-02-12T05:30:14ZengElsevierEcotoxicology and Environmental Safety0147-65132025-01-01290117759Phthalate exposure induces microRNA-5010/Nrf2-EGR1/GDF15 signaling expression in prostate cancerYuh-Shyan Tsai0Yeong-Chin Jou1Ian Seng Cheong2Hsiu-Ting Tung3Lin-Nei Hsu4Hsin-Tzu Tsai5Tzong-Shin Tzai6Department of Urology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan; Correspondence to: Department of Urology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, #138, Sheng-Li Road, Tainan 70403, Taiwan.Division of Urology, Department of Surgery, St Martin De Porres Hospital, Chia-Yi City, TaiwanDepartment of Urology, Ditmanson Medical Foundation Chia-Yi Christian Hospital, Chia-Yi, TaiwanDepartment of Urology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, TaiwanDepartment of Urology, An-Nan Hospital, China Medical University, Tainan, TaiwanDepartment of Urology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, TaiwanDepartment of Urology, An-Nan Hospital, China Medical University, Tainan, Taiwan; Corresponding author.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.http://www.sciencedirect.com/science/article/pii/S0147651325000958phthalate esterprostate cancermicroRNANrf-2GDF-15 |
| spellingShingle | Yuh-Shyan Tsai Yeong-Chin Jou Ian Seng Cheong Hsiu-Ting Tung Lin-Nei Hsu Hsin-Tzu Tsai Tzong-Shin Tzai Phthalate exposure induces microRNA-5010/Nrf2-EGR1/GDF15 signaling expression in prostate cancer Ecotoxicology and Environmental Safety phthalate ester prostate cancer microRNA Nrf-2 GDF-15 |
| title | Phthalate exposure induces microRNA-5010/Nrf2-EGR1/GDF15 signaling expression in prostate cancer |
| title_full | Phthalate exposure induces microRNA-5010/Nrf2-EGR1/GDF15 signaling expression in prostate cancer |
| title_fullStr | Phthalate exposure induces microRNA-5010/Nrf2-EGR1/GDF15 signaling expression in prostate cancer |
| title_full_unstemmed | Phthalate exposure induces microRNA-5010/Nrf2-EGR1/GDF15 signaling expression in prostate cancer |
| title_short | Phthalate exposure induces microRNA-5010/Nrf2-EGR1/GDF15 signaling expression in prostate cancer |
| title_sort | phthalate exposure induces microrna 5010 nrf2 egr1 gdf15 signaling expression in prostate cancer |
| topic | phthalate ester prostate cancer microRNA Nrf-2 GDF-15 |
| url | http://www.sciencedirect.com/science/article/pii/S0147651325000958 |
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