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.
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.
Ecotoxicol Environ Saf. 2024 Oct 1;284:116907. doi: 10.1016/j.ecoenv.2024.116907. Epub 2024 Aug 27.
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.
全氟壬酸（PFNA）是一种公认的环境内分泌干扰物，正越来越多地被用作全氟辛烷磺酸（PFOS）和全氟辛酸（PFOA）的替代品。尽管其应用日益广泛，但对于其潜在的致癌和进展作用及其潜在的分子机制的研究还很有限。早期的研究将全氟烷基和多氟烷基物质（PFAS）的暴露与人类乳腺癌和妇科癌症的进展联系起来，但对于潜在的机制，特别是在卵巢癌中，还缺乏明确的认识。我们的研究表明，在环境浓度（0.25-2mM）下，PFNA 对细胞增殖没有显著影响，但对卵巢癌细胞的侵袭和迁移有明显的促进作用。这导致上皮-间充质转化（EMT）标志物的改变，包括 Claudin1、Vimentin 和 Snail。值得注意的是，PFNA 暴露激活了 TGF-β/SMADs 信号通路。至关重要的是，通过泛素-蛋白酶体系统降解 SMAD7 成为 PFNA 诱导 EMT 的关键分子靶点，在小鼠模型中得到了证实。总之，这项研究提供了证据表明，环境相关浓度的 PFNA 可以通过蛋白酶体途径诱导 SMAD7 降解，进而激活 TGF-β/SMADs 信号通路，促进卵巢癌细胞的 EMT。这些结果阐明了 PFNA 暴露与卵巢癌转移之间的关联。
