YTHDF1介导的m6A修饰通过FZD7/ Wnt/β-连环蛋白途径促进卵巢癌顺铂耐药。

YTHDF1-mediated m6A modification promotes cisplatin resistance in ovarian cancer via the FZD7/Wnt/β-catenin pathway.

作者信息

Miao Jintian, Jiang Xinyan, Wang Siyun

机构信息

Department of Gynecology, First Affiliated Hospital of Harbin Medical University, No. 2705, Seventh Avenue, Qunli, Daoli District, Harbin, Heilongjiang Province, 151000, China.

出版信息

Apoptosis. 2025 Apr 26. doi: 10.1007/s10495-025-02094-0.

Abstract

Cisplatin resistance significantly hinders the efficacy of ovarian cancer treatment, presenting a major challenge in improving patient outcomes. This study identifies the m6A reader protein YTHDF1 as a key regulator of cisplatin resistance in ovarian cancer through its modulation of the FZD7/Wnt/β-catenin signaling pathway. Using cisplatin-resistant ovarian cancer cell lines (A2780/DDP and SKOV3/DDP), we observed elevated YTHDF1 expression, which positively correlated with tumor cell proliferation and migration. Silencing YTHDF1 reduced FZD7 expression, inhibited Wnt/β-catenin signaling, and restored cisplatin sensitivity both in vitro and in vivo. Mechanistic investigations revealed that YTHDF1 binds to m6A-modified FZD7 mRNA, enhancing its stability and translation. Functional studies in xenograft mouse models demonstrated that targeting YTHDF1 suppressed tumor growth and enhanced apoptosis in cisplatin-resistant ovarian cancer cells. These findings highlight the YTHDF1-FZD7 axis as a novel therapeutic target for overcoming cisplatin resistance, paving the way for improved treatment strategies in ovarian cancer.

摘要

顺铂耐药显著阻碍卵巢癌治疗效果,是改善患者预后的一大挑战。本研究通过调节FZD7/Wnt/β-连环蛋白信号通路,确定m6A阅读蛋白YTHDF1是卵巢癌顺铂耐药的关键调节因子。使用顺铂耐药的卵巢癌细胞系(A2780/DDP和SKOV3/DDP),我们观察到YTHDF1表达升高,其与肿瘤细胞增殖和迁移呈正相关。沉默YTHDF1可降低FZD7表达,抑制Wnt/β-连环蛋白信号通路,并在体外和体内恢复顺铂敏感性。机制研究表明,YTHDF1与m6A修饰的FZD7 mRNA结合,增强其稳定性和翻译。在异种移植小鼠模型中的功能研究表明,靶向YTHDF1可抑制顺铂耐药卵巢癌细胞的肿瘤生长并增强凋亡。这些发现突出了YTHDF1-FZD7轴作为克服顺铂耐药的新型治疗靶点,为改善卵巢癌治疗策略铺平了道路。

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