Zhou Mingyi, Gao Yan, Zhang Yong, He Lian, Gao Bo, Zhang Yue, Claret Francois X, Calin George A, Wang Danbo
Department of Gynecology, Cancer Hospital of China Medical University, Cancer Hospital of Dalian University of Technology, Liaoning Cancer Hospital & Institute, No.44 Xiaoheyan Road, Dadong District, Shenyang, 110042, Liaoning Province, China.
Department of Pathology, Cancer Hospital of China Medical University, Liaoning Cancer Hospital & Institute, Shenyang, 110042, China.
Mol Cancer. 2025 Aug 21;24(1):218. doi: 10.1186/s12943-025-02424-5.
Lymph node metastasis is a key driver of poor outcomes in cervical cancer. However, the molecular mechanisms of circular RNAs (circRNAs) driving cervical cancer lymph node metastasis remain unclear.
We identified circZFR, fatty acid synthase (FASN) and YTH N6-methyladenosine RNA binding protein F3 (YTHDF3) protein expression in the cervical cancer patients with long and short disease-free survival (DFS). Functional experiments were performed to investigate the function of circZFR, FASN and YTHDF3 on cell migration and invasion. MeRIP-qPCR, RNA pulldown, RNA Immunoprecipitation (RIP), and Co-Immunoprecipitation (Co-IP) assays were executed to investigate the mechanism of circZFR regulating FASN protein expression.
Our study reveals that elevated FASN protein is closely linked to metastasis and reduced survival, and identified a regulatory mechanism involving circular RNAs. We identified circZFR as a crucial regulator, significantly enhancing FASN protein expression. CircZFR overexpression was significantly correlated with accelerated lymph node metastasis and shortened DFS. Mechanistically, circZFR binds to the mA reader protein YTHDF3, facilitating mA recognition on FASN mRNA and recruiting the translation initiator eIF4A3, thereby boosting FASN translation.
These findings establish circZFR as a pivotal driver of cervical cancer progression and highlight its inhibition as a promising therapeutic strategy.
淋巴结转移是宫颈癌预后不良的关键驱动因素。然而，环状RNA（circRNA）驱动宫颈癌淋巴结转移的分子机制仍不清楚。
我们鉴定了无病生存期长短不同的宫颈癌患者中circZFR、脂肪酸合酶（FASN）和YTH N6-甲基腺苷RNA结合蛋白F3（YTHDF3）的蛋白表达。进行功能实验以研究circZFR、FASN和YTHDF3对细胞迁移和侵袭的作用。开展甲基化RNA免疫沉淀定量PCR（MeRIP-qPCR）、RNA下拉、RNA免疫沉淀（RIP）和免疫共沉淀（Co-IP）实验，以探究circZFR调节FASN蛋白表达的机制。
我们的研究表明，FASN蛋白水平升高与转移和生存期缩短密切相关，并确定了一种涉及环状RNA的调控机制。我们鉴定出circZFR是一个关键调节因子，可显著增强FASN蛋白表达。circZFR过表达与淋巴结转移加速和无病生存期缩短显著相关。机制上，circZFR与m6A阅读蛋白YTHDF3结合，促进对FASN mRNA的m6A识别，并招募翻译起始因子eIF4A3，从而促进FASN的翻译。
这些发现确立了circZFR作为宫颈癌进展的关键驱动因素，并突出了对其抑制作为一种有前景的治疗策略。
