Bell Research Center, Department of Obstetrics and Gynecology Collaborative Research, Nagoya University Graduate School of Medicine, Tsurumai-cho, Showa-ku, Nagoya, Japan; Bell Research Center for Reproductive Health and Cancer, Medical Corporation Kishokai, Nagoya, Aichi, Japan.
Bell Research Center, Department of Obstetrics and Gynecology Collaborative Research, Nagoya University Graduate School of Medicine, Tsurumai-cho, Showa-ku, Nagoya, Japan; Bell Research Center for Reproductive Health and Cancer, Medical Corporation Kishokai, Nagoya, Aichi, Japan.
Lab Invest. 2023 Mar;103(3):100025. doi: 10.1016/j.labinv.2022.100025. Epub 2023 Jan 10.
Although platinum-combination chemotherapy shows a high response rate at the primary site, epithelial ovarian cancer (EOC) treatment remains challenging because of tumor recurrence and metastasis. Recent studies have revealed that chemotherapy paradoxically promotes cancer cell survival, proliferation, and metastasis, although the reason for this remains unclear. The underlying molecular mechanisms that contribute to chemotherapy-induced metastasis need to be elucidated to establish effective therapeutic strategies. Acute kidney injury is a known side effect of cisplatin treatment, and kidney dysfunction results in the accumulation of uremic toxins in the serum. The present study aimed to investigate whether indoxyl sulfate (IS), a representative uremic toxin, affects the pathophysiology of EOC. In this study, IS reduced the expression of Mas receptor (MasR) in cultured human EOC cells. Both knockdown of the aryl hydrocarbon receptor (AhR), which is an intracellular IS receptor, and inhibition of AhR function suppressed IS-mediated downregulation of MasR in SK-OV-3 cells. IS induced the phosphorylation of signal transducer and activator of transcription 3 (STAT3) in an AhR-dependent manner. Inhibition of the STAT3 pathway or reactive oxygen species production suppressed the IS-mediated reduction of MasR. IS stimulated cell migration and invasion of SK-OV-3 cells in an AhR-dependent manner. Cisplatin-nephropathy model mice exhibited elevated levels of serum IS accompanied by elevated levels of blood urea nitrogen and serum creatinine. Furthermore, intraperitoneal administration of IS in mice promoted tumor growth and metastasis. Finally, we found that the MasR agonist Ang-(1-7) suppressed the IS-mediated effects on cell proliferation, migration, and invasion of SK-OV-3 cells. However, the knockdown of MasR expression by specific small interfering RNA in the absence of IS resulted in only minimal promotion of cell migration and invasion. These findings demonstrate that IS promotes malignancy in ovarian cancer via AhR-mediated downregulation of MasR function, whereas Ang-(1-7) attenuates this effect, thereby suggesting that Ang-(1-7) could provide a future treatment strategy for this cancer type.
虽然铂类联合化疗在原发性部位显示出高反应率，但由于肿瘤复发和转移，上皮性卵巢癌 (EOC) 的治疗仍然具有挑战性。最近的研究表明，尽管原因尚不清楚，但化疗反而促进了癌细胞的存活、增殖和转移。需要阐明导致化疗诱导转移的潜在分子机制，以建立有效的治疗策略。顺铂治疗已知会导致急性肾损伤，而肾功能障碍导致血清中尿毒症毒素的积累。本研究旨在探讨是否靛蓝硫酸盐 (IS)，一种代表性的尿毒症毒素，会影响 EOC 的病理生理学。在这项研究中，IS 降低了培养的人 EOC 细胞中 Mas 受体 (MasR) 的表达。AhR 的敲低 (AhR，IS 的细胞内受体) 和 AhR 功能的抑制均抑制了 IS 介导的 SK-OV-3 细胞中 MasR 的下调。IS 以 AhR 依赖的方式诱导信号转导和转录激活因子 3 (STAT3) 的磷酸化。STAT3 途径的抑制或活性氧的产生抑制了 IS 介导的 MasR 减少。IS 以 AhR 依赖的方式刺激 SK-OV-3 细胞的迁移和侵袭。顺铂肾病模型小鼠表现出血清 IS 水平升高，同时伴有血尿素氮和血清肌酐水平升高。此外，IS 在小鼠体内的腹腔内给药促进了肿瘤的生长和转移。最后，我们发现 MasR 激动剂 Ang-(1-7) 抑制了 IS 对 SK-OV-3 细胞增殖、迁移和侵袭的作用。然而，在不存在 IS 的情况下，特异性小干扰 RNA 对 MasR 表达的敲低仅导致细胞迁移和侵袭的最小促进。这些发现表明，IS 通过 AhR 介导的 MasR 功能下调促进卵巢癌的恶性程度，而 Ang-(1-7) 减弱了这种作用，提示 Ang-(1-7) 可能为这种癌症类型提供未来的治疗策略。
