Environmentally relevant concentration PFNA promotes degradation of SMAD7 to drive progression of ovarian cancer via TGF-β/SMADs signaling pathway

Jiamin Zhong; Lihuan Zhang; Kelie Chen; Xiaoyu Yuan; Zhenyan Cui; Song Tang; Fang Zheng; Ying Li; Paul Héroux; Yihua Wu; Dajing Xia

Ecotoxicology and Environmental Safety (Oct 2024)

Environmentally relevant concentration PFNA promotes degradation of SMAD7 to drive progression of ovarian cancer via TGF-β/SMADs signaling pathway

Jiamin Zhong,
Lihuan Zhang,
Kelie Chen,
Xiaoyu Yuan,
Zhenyan Cui,
Song Tang,
Fang Zheng,
Ying Li,
Paul Héroux,
Yihua Wu,
Dajing Xia

Affiliations

Jiamin Zhong: Department of Toxicology of School of Public Health and Department of Gynecologic Oncology of Women's Hospital, Zhejiang University School of Medicine, Hangzhou, China; Department of Gastroenterology, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310009, China
Lihuan Zhang: Department of Toxicology of School of Public Health and Department of Gynecologic Oncology of Women's Hospital, Zhejiang University School of Medicine, Hangzhou, China; The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou City, Zhejiang Province 310003, China
Kelie Chen: Department of Toxicology of School of Public Health and Department of Gynecologic Oncology of Women's Hospital, Zhejiang University School of Medicine, Hangzhou, China; Department of Gynecology and Obstetrics, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang Province 310003, China
Xiaoyu Yuan: Department of Toxicology of School of Public Health and Department of Gynecologic Oncology of Women's Hospital, Zhejiang University School of Medicine, Hangzhou, China
Zhenyan Cui: Department of Toxicology of School of Public Health and Department of Gynecologic Oncology of Women's Hospital, Zhejiang University School of Medicine, Hangzhou, China
Song Tang: Department of Toxicology of School of Public Health and Department of Gynecologic Oncology of Women's Hospital, Zhejiang University School of Medicine, Hangzhou, China
Fang Zheng: Department of Toxicology of School of Public Health and Department of Gynecologic Oncology of Women's Hospital, Zhejiang University School of Medicine, Hangzhou, China; Department of Gynecology and Obstetrics, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang Province 310003, China
Ying Li: Department of Epidemiology, Biostatistics and Occupational Health, 2001 McGill University, Suite 1200, Montreal H3A 1G1, Canada
Paul Héroux: Department of Epidemiology, Biostatistics and Occupational Health, 2001 McGill University, Suite 1200, Montreal H3A 1G1, Canada
Yihua Wu: Department of Toxicology of School of Public Health and Department of Gynecologic Oncology of Women's Hospital, Zhejiang University School of Medicine, Hangzhou, China; Correspondence to: Department of Toxicology, School of Public Health, Women's Hospital, School of Medicine, Zhejiang University, Hangzhou 310058, China.
Dajing Xia: Department of Toxicology of School of Public Health and Department of Gynecologic Oncology of Women's Hospital, Zhejiang University School of Medicine, Hangzhou, China; Correspondence to: Department of Toxicology, School of Public Health, Women's Hospital, School of Medicine, Zhejiang University, Hangzhou 310058, China.

Journal volume & issue: Vol. 284
p. 116907

Abstract

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Perfluorononanoic acid (PFNA), an acknowledged environmental endocrine disruptor, is increasingly utilized as a substitute for perfluorooctanesulfonic acid (PFOS) and perfluorooctanoic acid (PFOA). Despite its growing use, limited research has been conducted to investigate its potential impact on tumorigenesis and progression, and the potential molecular mechanisms. Earlier studies linked perfluoroalkyl and polyfluoroalkyl substances (PFAS) exposure to breast and gynecological cancer progression in humans, lacking a clear understanding of the underlying mechanisms, notably in ovarian cancer. Our investigation into PFNA's effects at environmental concentrations (0.25–2 mM) showed no significant impact on cell proliferation but a notable increase in invasion and migration of ovarian cancer cells. This led to alterations in epithelial-mesenchymal transition (EMT) markers, including Claudin1, Vimentin, and Snail. Notably, PFNA exposure activated the TGF-β/SMADs signaling pathway. Crucially, SMAD7 degradation through the ubiquitin-proteasome system emerged as PFNA's pivotal molecular target for inducing EMT, corroborated in mouse models. In summary, this study presented evidence that environmentally relevant concentrations of PFNA could induce SMAD7 degradation via the proteasome pathway, subsequently activating the TGF-β/SMADs signaling pathway, and promoting EMT in ovarian cancer. These results illuminated the association between PFNA exposure and metastasis of ovarian cancer.

Published in Ecotoxicology and Environmental Safety

ISSN: 0147-6513 (Print); 1090-2414 (Online)
Publisher: Elsevier
Country of publisher: United States
LCC subjects: Technology: Environmental technology. Sanitary engineering: Environmental pollution; Geography. Anthropology. Recreation: Environmental sciences
Website: https://www.journals.elsevier.com/ecotoxicology-and-environmental-safety

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