Guo Zhengyang, Li Yinjia, Guo Yunyun, Zhang Aosong, Huo Xiao, Song Ying, Li Bing, Tang Yuanjun, He Tianhui, Liu Tong, Xue Lixiang, Qu Yi, Song Jiagui
Cancer Center of Peking University Third Hospital, Beijing, 100191, China.
Center of Basic Medical Research, Institute of Medical Innovation and Research, Peking University Third Hospital, Beijing, 100191, China.
J Ovarian Res. 2025 Aug 11;18(1):180. doi: 10.1186/s13048-025-01763-7.
Ovarian cancer represents the most aggressive and lethal gynecological cancer, frequently demonstrating a distinct propensity for abdominal metastasis. Malignant ascites caused by abdominal metastasis provide a tumor microenvironment (TME) in ovarian cancer. Notably, oleic acid is abundant in ovarian cancer ascites, though its functional significance in TME modulation and tumor metastatic regulation remains poorly characterized. Stearoyl-CoA desaturase 1 (SCD1) is the key enzyme in the synthesis of oleic acid. Our study systematically explores the pathological role of oleic acid and evaluates the therapeutic effects of SCD1 inhibitor in ovarian cancer progression.
Oleic acid treatment significantly enhanced proliferation of ovarian cancer cells and patient-derived organoids. Remarkably, oleic acid also increased membrane fluidity and promoted cell migration. Mechanistically, TGFβ-Smad3 signaling cascade is selectively activated by oleic acid, and inhibited by SCD1 suppression. Importantly, activation of Smad3 caused by oleic acid treatment triggered epithelial-mesenchymal transition of ovarian cancer cells. Clinical relevance was established that SCD1 expression was positively correlated with the activity of Smad3 in ovarian cancer tissues. Finally, in vivo studies showed that SCD1 inhibitor treatment suppressed tumor progression during intraperitoneal dissemination.
This study provides novel insights into the supporting role of oleic acid in fueling tumor proliferation and metastasis, mechanistically associated with its specific activation of TGFβ-Smad3 signaling. Therapeutically, pharmacological targeting oleic acid synthesis by SCD1 inhibitor emerges as a promising strategy for precision oncology in ovarian cancer management.
卵巢癌是最具侵袭性和致死性的妇科癌症，常表现出明显的腹部转移倾向。腹部转移引起的恶性腹水为卵巢癌提供了肿瘤微环境（TME）。值得注意的是，油酸在卵巢癌腹水中含量丰富，但其在TME调节和肿瘤转移调控中的功能意义仍不清楚。硬脂酰辅酶A去饱和酶1（SCD1）是油酸合成的关键酶。我们的研究系统地探讨了油酸的病理作用，并评估了SCD1抑制剂对卵巢癌进展的治疗效果。
油酸处理显著增强了卵巢癌细胞和患者来源类器官的增殖。值得注意的是，油酸还增加了膜流动性并促进了细胞迁移。机制上，TGFβ-Smad3信号级联被油酸选择性激活，并被SCD1抑制所抑制。重要的是，油酸处理引起的Smad3激活触发了卵巢癌细胞的上皮-间质转化。建立了临床相关性，即SCD1表达与卵巢癌组织中Smad3的活性呈正相关。最后，体内研究表明，SCD1抑制剂治疗可抑制腹腔播散期间的肿瘤进展。
本研究为油酸在促进肿瘤增殖和转移中的支持作用提供了新的见解，其机制与其对TGFβ-Smad3信号的特异性激活有关。在治疗上，通过SCD1抑制剂对油酸合成进行药理靶向，成为卵巢癌精准肿瘤治疗的一种有前景的策略。
