Li Mai-Dong, Shan Ben-Jie, Wang Lei, Gao Shuang, Hao Li, Yu Hai-Yang, Pan Yue-Yin
Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China.
Department of Medical Oncology, The First Affiliated Hospital of University of Science and Technology of China, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, China.
Front Oncol. 2025 Jun 26;15:1608574. doi: 10.3389/fonc.2025.1608574. eCollection 2025.
Breast cancer is characterized as highly heterogenous and is a representative model to understand how molecular features of tumor biology determine therapeutic strategy. LINC01133 exhibits opposing expressing patterns across different breast cancer subtypes, yet its roles and mechanisms in ER breast cancer remain a loaded question.
The expression of LINC01133 was initially assessed utilizing a public dataset TCGA and subsequently validated within clinical samples through RT-qPCR and hybridization (ISH). To determine the role of LINC01133, various assays, including colony formation, Transwell, 5-ethynyl-2'-deoxyuridine (EdU) labeling, and mouse xenograft experiments, were performed. Additionally, RNA immunoprecipitation (RIP), RNA pull-down, mass spectrometry (MS), and RNA stability assays were conducted to elucidate its mechanisms.
LINC01133 was dramatically downregulated in ER breast cancer, which results in unfavorable prognosis. Functionally, LINC01133 inhibited migration and invasion and metastasis of ER breast cancer cells. Mechanistically, LINC01133 can directly interact with IGF2BP2 protein promoting its ubiquitination and degradation. The downregulation of LINC01133 was mediated by mA modification, catalyzed by METTL3 and recognized by YTHDF2, causing half-life reduction and accelerated degradation of LINC01133.
Our findings revealed the downregulation of LINC01133 in ER breast cancer and provided novel insight to the role of METTL3/YTHDF2/LINC01133/IGF2BP2 axis in ER breast cancer, which might offer a novel perspective in the design and development of novel anticancer drugs.
乳腺癌具有高度异质性，是理解肿瘤生物学分子特征如何决定治疗策略的代表性模型。LINC01133在不同乳腺癌亚型中表现出相反的表达模式，但其在雌激素受体（ER）阳性乳腺癌中的作用和机制仍是一个有待解决的问题。
首先利用公共数据集TCGA评估LINC01133的表达，随后通过逆转录定量聚合酶链反应（RT-qPCR）和原位杂交（ISH）在临床样本中进行验证。为了确定LINC01133的作用，进行了多种实验，包括集落形成实验、Transwell实验、5-乙炔基-2'-脱氧尿苷（EdU）标记实验和小鼠异种移植实验。此外，还进行了RNA免疫沉淀（RIP）、RNA下拉实验、质谱分析（MS）和RNA稳定性实验以阐明其机制。
LINC01133在ER阳性乳腺癌中显著下调，这导致不良预后。在功能上，LINC01133抑制ER阳性乳腺癌细胞的迁移、侵袭和转移。机制上，LINC01133可直接与胰岛素样生长因子2结合蛋白2（IGF2BP2）相互作用，促进其泛素化和降解。LINC01133的下调由N6-甲基腺苷（m6A）修饰介导，该修饰由甲基转移酶样蛋白3（METTL3）催化并被YTH结构域家族蛋白2（YTHDF2）识别，导致LINC01133半衰期缩短并加速降解。
我们的研究结果揭示了LINC01133在ER阳性乳腺癌中的下调，并为METTL3/YTHDF2/LINC01133/IGF2BP2轴在ER阳性乳腺癌中的作用提供了新的见解，这可能为新型抗癌药物的设计和开发提供新的视角。
