Li Hongfeng, Bian Jia, Liu Minjie, Wang Yijie, Shang Yapping, Zheng Yu, Li Xuehe
Obstetrics and Gynecology, The Affiliated People's Hospital of Ningbo University, 251 East Baizhang Road, Ningbo, 315040, Zhejiang, China.
J Mol Histol. 2025 Jan 22;56(1):72. doi: 10.1007/s10735-024-10327-w.
Long non-coding RNAs (lncRNAs) have emerged as pivotal regulatory molecules in cancer biology. Among these, long intergenic non-protein coding RNA 02418 (LINC02418), a recently identified lncRNA, has been linked to endometrial cancer (EC), although its function and operational mechanisms are largely unclear. The present investigation aims to elucidate the molecular mechanism through which LINC02418 influences EC pathogenesis. We employed Western blotting and quantitative real-time PCR to analyze Ras protein specific guanine nucleotide releasing factor 1 (RASGRF1) and LINC02418 expression profiles in EC tissues and cell lines. Functional analyses, including cell proliferation, migration, and invasion assays, were conducted to evaluate the impact of LINC02418 overexpression on EC cells. Xenograft mouse models were established for in vivo validation. The molecular interactions between LINC02418, miR-494-3p, and RASGRF1 were characterized using luciferase reporter and RNA pull-down assays. LINC02418 expression was significantly downregulated in EC tissues and cell lines compared to their normal counterparts. Forced expression of LINC02418 significantly suppressed EC cell proliferation, migration, and invasion in vitro. In xenograft models, LINC02418 overexpression resulted in reduced tumor burden and enhanced cell death. Mechanistically, LINC02418 enhanced RASGRF1 expression by sequestering miR-494-3p, a finding substantiated by RNA pull-down assays. The tumor-suppressive effects of LINC02418 were partially reversed by RASGRF1 silencing and miR-494-3p overexpression. Clinical analyses revealed that reduced RASGRF1 expression correlated with poor histological differentiation, advanced tumor stages, and decreased overall survival in EC patients. Our findings establish LINC02418 as a tumor suppressor that regulates EC progression through modulation of the miR-494-3p/RASGRF1 axis, highlighting its potential as a therapeutic target in EC treatment.
长链非编码RNA（lncRNAs）已成为癌症生物学中的关键调控分子。其中，长链基因间非蛋白质编码RNA 02418（LINC02418）是一种最近发现的lncRNA，它与子宫内膜癌（EC）有关，尽管其功能和作用机制尚不清楚。本研究旨在阐明LINC02418影响EC发病机制的分子机制。我们采用蛋白质免疫印迹法和定量实时聚合酶链反应分析EC组织和细胞系中Ras蛋白特异性鸟嘌呤核苷酸释放因子1（RASGRF1）和LINC02418的表达谱。进行了包括细胞增殖、迁移和侵袭试验在内的功能分析，以评估LINC02418过表达对EC细胞的影响。建立了异种移植小鼠模型进行体内验证。使用荧光素酶报告基因和RNA下拉试验来表征LINC02418、miR-494-3p和RASGRF1之间的分子相互作用。与正常组织和细胞系相比，EC组织和细胞系中LINC02418的表达显著下调。LINC02418的强制表达显著抑制了EC细胞在体外的增殖、迁移和侵袭。在异种移植模型中，LINC02418过表达导致肿瘤负荷降低和细胞死亡增加。从机制上讲，LINC02418通过隔离miR-494-3p增强了RASGRF1的表达，这一发现通过RNA下拉试验得到证实。RASGRF1沉默和miR-494-3p过表达部分逆转了LINC02418的肿瘤抑制作用。临床分析显示，EC患者中RASGRF1表达降低与组织学分化差、肿瘤分期进展和总生存率降低相关。我们的研究结果表明，LINC02418是一种肿瘤抑制因子，通过调节miR-494-3p/RASGRF1轴来调节EC进展，突出了其作为EC治疗中治疗靶点的潜力。
