Participation of Long Noncoding RNA FOXP4-AS1 in the Development and Progression of Endometrioid Carcinoma with Epigenetically Silencing DUSP5.

IF 2.4 4区 医学 Q3 MEDICINE, RESEARCH & EXPERIMENTAL
Cancer Biotherapy and Radiopharmaceuticals Pub Date : 2024-08-01 Epub Date: 2024-03-20 DOI:10.1089/cbr.2023.0039
Leilei Liu, Jingyun Zhao, Hui Guo, Jingde Jia, Li Shi, Jing Ma, Zhengmao Zhang
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引用次数: 0

Abstract

Background: Long noncoding RNAs (lncRNAs), as emerging regulators of a wide variety of biological processes via diverse mechanisms, have been demonstrated to be of increasing importance in biology. Genome-wide association studies of tumor samples have identified several lncRNAs as either oncogenes or tumor suppressors in various types of cancers. In recent years, the importance of lncRNAs, especially in endometrioid cancer (EEC), has become increasingly well understood. The lncRNA Forkhead box P4 antisense RNA 1 (FOXP4-AS1) has been reported to fulfill roles in several types of cancers; however, the main biological function and associated underlying molecular mechanism of FOXP4-AS1 in EEC have yet to be fully elucidated. The present study therefore aimed to investigate how RNA FOXP4-AS1 may participate in the development and progression of endometrioid carcinoma tissues. Materials and Methods: In the present study, the expression level of FOXP4-AS1 was investigated in endometrioid carcinoma tissues and matching nearby normal endometrial tissues collected from patients receiving surgery at the hospital. A series of molecular biological assays were performed to investigate the effect of FOXP4-AS1 on cell proliferation, cell migration, and cell invasion. Results: An increased concentration of FOXP4-AS1 was identified in endometrioid carcinoma samples and cell lines compared with the corresponding controls, and this lncRNA was found to be positively correlated with advanced FIGO stages in patients with endometrial cancer. Furthermore, knocking down endogenous FOXP4-AS1 led to a significant reduction in the colony formation number and a significant inhibition of cell proliferation, cell migration, and cell invasion in endometrioid carcinoma cells. Moreover, dual-specificity phosphatase 5 (DUSP5), which is lowly expressed in endometrioid carcinoma tissues cells and negatively modulated by FOXP4-AS1, was identified as the downstream target molecule of FOXP4-AS1. Subsequently, the mechanistic experiments confirmed that, through binding to enhancer of zeste homolog 2 (EZH2; one of the catalytic subunits of polycomb repressive complex 2 [PRC2]), FOXP4-AS1 could epigenetically suppress the expression of DUSP5. Finally, the oncogenic function of the FOXP4-AS1/EZH2/DUSP5 axis in endometrioid carcinoma was confirmed via rescue assays. Conclusions: The findings of the present study have highlighted how FOXP4-AS1 fulfills an oncogenic role in endometrioid carcinoma, and targeting FOXP4-AS1 and its pathway may provide new biomarkers for patients with endometrioid carcinoma.

长非编码 RNA FOXP4-AS1 通过表观遗传沉默 DUSP5 参与子宫内膜样癌的发生和发展
背景:长非编码 RNA(lncRNA)作为通过不同机制调控各种生物过程的新兴调控因子,已被证明在生物学中的重要性与日俱增。对肿瘤样本进行的全基因组关联研究发现,一些 lncRNA 在各种类型的癌症中可作为致癌基因或肿瘤抑制因子。近年来,人们对lncRNA的重要性,尤其是在子宫内膜癌(EEC)中的重要性,有了越来越深入的了解。据报道,lncRNA叉头盒P4反义RNA 1(FOXP4-AS1)在多种癌症中发挥着作用;然而,FOXP4-AS1在EEC中的主要生物学功能及其相关的分子机制尚未完全阐明。材料和方法:因此,本研究旨在探讨 RNA FOXP4-AS1 如何参与子宫内膜样癌组织的发育和进展。为了达到这一目的,本研究调查了子宫内膜样癌组织和相匹配的邻近正常子宫内膜组织中 FOXP4-AS1 的表达水平,并进行了一系列分子生物学检测,以研究 FOXP4-AS1 对细胞增殖、细胞迁移和细胞侵袭等的影响。结果显示与相应的对照组相比,子宫内膜样癌样本和细胞系中的FOXP4-AS1浓度升高,而且该lncRNA与子宫内膜癌患者的FIGO晚期呈正相关。此外,敲除内源性 FOXP4-AS1 能显著减少子宫内膜样癌细胞的集落形成数量,并显著抑制细胞增殖、细胞迁移和细胞侵袭。此外,双特异性磷酸酶5(DUSP5)被确定为FOXP4-AS1的下游靶分子,它在子宫内膜样癌组织细胞中低表达,并受FOXP4-AS1的负调控。随后,机理实验证实,FOXP4-AS1 可通过与泽斯特同源增强子 2(EZH2,多聚核抑制复合体 2 [PRC2] 催化亚基之一)结合,从表观遗传学上抑制 DUSP5 的表达。最后,通过挽救实验证实了 FOXP4-AS1/EZH2/DUSP5 轴在子宫内膜样癌中的致癌功能。结论:本研究的发现强调了 FOXP4-AS1 在子宫内膜样癌中的致癌作用,靶向 FOXP4-AS1 及其通路可能为子宫内膜样癌患者提供新的生物标记物。
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来源期刊
CiteScore
7.80
自引率
2.90%
发文量
87
审稿时长
3 months
期刊介绍: Cancer Biotherapy and Radiopharmaceuticals is the established peer-reviewed journal, with over 25 years of cutting-edge content on innovative therapeutic investigations to ultimately improve cancer management. It is the only journal with the specific focus of cancer biotherapy and is inclusive of monoclonal antibodies, cytokine therapy, cancer gene therapy, cell-based therapies, and other forms of immunotherapies. The Journal includes extensive reporting on advancements in radioimmunotherapy, and the use of radiopharmaceuticals and radiolabeled peptides for the development of new cancer treatments.
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