双酚A（BPA）是一种普遍存在的环境异生物，影响全球数百万人。长期以来，BPA一直被认为会促进卵巢癌发生，但其有害的机制靶点尚不清楚。癌干细胞（CSCs）被认为是肿瘤起始和进展的触发器。在这里，我们首次展示，纳摩尔（环境相关）浓度的BPA可以显著增加卵巢CSCs的形成和扩张。这种效应在雌激素受体（ER）阳性和ER缺失的卵巢癌细胞中都观察到，表明它独立于经典ERs。相反，该信号是通过替代的ER G蛋白偶联受体30（GPR30）介导的，而不是雌激素相关受体α和γ。此外，我们报道了BPA在调控Exportin-5方面的新角色，从而通过miR-21导致microRNA生物合成的失调。使用GPR30 siRNA或拮抗剂抑制GPR30表达或活性，显著抑制了卵巢CSCs的形成。同样，通过表达Exportin-5 siRNA可以逆转CSCs表型。这些结果首次确定了非经典ER和microRNA失调作为BPA在低、生理水平下对CSCs功能的新调控因子，可能是其在卵巢癌中具有重要肿瘤促进性质的基础。© 2023 The Authors. Journal of Cellular and Molecular Medicine published by Foundation for Cellular and Molecular Medicine and John Wiley & Sons Ltd.

Bisphenol A (BPA) is a ubiquitous environmental xenobiotic impacting millions of people worldwide. BPA has long been proposed to promote ovarian carcinogenesis, but the detrimental mechanistic target remains unclear. Cancer stem cells (CSCs) are considered as the trigger of tumour initiation and progression. Here, we show for the first time that nanomolar (environmentally relevant) concentration of BPA can markedly increase the formation and expansion of ovarian CSCs concomitant. This effect is observed in both oestrogen receptor (ER)-positive and ER-defective ovarian cancer cells, suggesting that is independent of the classical ERs. Rather, the signal is mediated through alternative ER G-protein-coupled receptor 30 (GPR30), but not oestrogen-related receptor α and γ. Moreover, we report a novel role of BPA in the regulation of Exportin-5 that led to dysregulation of microRNA biogenesis through miR-21. The use of GPR30 siRNA or antagonist to inhibit GPR30 expression or activity, respectively, resulted in significant inhibition of ovarian CSCs. Similarly, the CSCs phenotype can be reversed by expression of Exportin-5 siRNA. These results identify for the first time non-classical ER and microRNA dysregulation as novel mediators of low, physiological levels of BPA function in CSCs that may underlie its significant tumour-promoting properties in ovarian cancer.© 2023 The Authors. Journal of Cellular and Molecular Medicine published by Foundation for Cellular and Molecular Medicine and John Wiley & Sons Ltd.