Numerous studies have characterized the critical role of circular RNAs(circRNAs)as regulatory factors in the progression of multiple cancers.However,the biological functions of circRNAs and their underlying molecular ...Numerous studies have characterized the critical role of circular RNAs(circRNAs)as regulatory factors in the progression of multiple cancers.However,the biological functions of circRNAs and their underlying molecular mechanisms in the progression of uveal melanoma(UM)remain enigmatic.In this study,we identified a novel circRNA,circ_0053943,through re-analysis of UM microarray data and quantitative RT-PCR.Circ_0053943 was found to be upregulated in UM and to promote the proliferation and metastatic ability of UM cells in both in vitro and in vivo settings.Mechanistically,circ_0053943 was observed to bind to the KH1 and KH2 domains of insulin-like growth factor 2 mRNA-binding protein 3(IGF2BP3),thereby enhancing the function of IGF2BP3 by stabilizing its target mRNA.RNA sequencing assays identified epidermal growth factor receptor(EGFR)as a target gene of circ_0053943 and IGF2BP3 at the transcriptional level.Rescue assays demonstrated that circ_0053943 exerts its biological function by stabilizing EGFR mRNA and regulating the downstream mitogen-activated protein kinase/extracellular signal-regulated kinase(MAPK/ERK)signaling pathway.Collectively,circ_0053943 may promote UM progression by stabilizing EGFR mRNA and activating the MAPK/ERK signaling pathway through the formation of a circ_0053943/IGF2BP3/EGFR RNA-protein ternary complex,thus providing a potential biomarker and therapeutic target for UM.展开更多
文摘目的:子宫内膜癌是女性生殖系统常见的恶性肿瘤,以子宫内膜样癌(endometrioid adenocarcinoma,EEC)最常见,其发病机制目前尚不清楚,已有研究证明环状RNA(circular RNA,circRNA)的表达与EEC的进展有关。本研究旨在检测hsa_circ_0007067在EEC中的表达,并探讨Hsa_circ_0007067与EEC临床病理特征的关系。方法:应用高通量测序分析2例EEC组织和2例正常子宫内膜组织基因表达水平,以|log2(Fold changes)|≥1.5且P<0.05为筛选标准,选择下调最显著的hsa_circ_0007067为研究对象,应用实时聚合酶链反应(real-time PCR)检测36例EEC组织(EEC组)和36例正常子宫内膜组织(对照组)中hsa_circ_0007067的相对表达量。生物信息学分析预测hsa_circ_0007067的结合位点和编码能力。结果:EEC组中hsa_circ_0007067表达水平显著低于对照组(P<0.05),且表达水平与国际妇产科联盟(Inter-national Federation of Gynecology and Obstetrics,FIGO)分期和组织分化程度有关;受试者操作特征(receiver operating characteristic,ROC)曲线显示曲线下面积(area under curve,AUC)为0.936,敏感度为0.833,特异度为0.889,最佳截断值为0.722,差异具有统计学意义(P<0.05)。Hsa_circ_0007067具有翻译成多肽的潜能,circbank数据库预测其miRNA潜在结合位点共24个。结论:Hsa_circ_0007067与EEC的发生、发展相关,可能通过与下游靶基因miRNA结合或编码蛋白质功能影响EEC的进程,有望作为EEC早期筛查和判断预后的分子指标。
基金supported by the National Natural Science Foundation of China(Nos.82273159 and 82171838)the Jiangsu Province’s Science and Technology Project(No.BE2020722).
文摘Numerous studies have characterized the critical role of circular RNAs(circRNAs)as regulatory factors in the progression of multiple cancers.However,the biological functions of circRNAs and their underlying molecular mechanisms in the progression of uveal melanoma(UM)remain enigmatic.In this study,we identified a novel circRNA,circ_0053943,through re-analysis of UM microarray data and quantitative RT-PCR.Circ_0053943 was found to be upregulated in UM and to promote the proliferation and metastatic ability of UM cells in both in vitro and in vivo settings.Mechanistically,circ_0053943 was observed to bind to the KH1 and KH2 domains of insulin-like growth factor 2 mRNA-binding protein 3(IGF2BP3),thereby enhancing the function of IGF2BP3 by stabilizing its target mRNA.RNA sequencing assays identified epidermal growth factor receptor(EGFR)as a target gene of circ_0053943 and IGF2BP3 at the transcriptional level.Rescue assays demonstrated that circ_0053943 exerts its biological function by stabilizing EGFR mRNA and regulating the downstream mitogen-activated protein kinase/extracellular signal-regulated kinase(MAPK/ERK)signaling pathway.Collectively,circ_0053943 may promote UM progression by stabilizing EGFR mRNA and activating the MAPK/ERK signaling pathway through the formation of a circ_0053943/IGF2BP3/EGFR RNA-protein ternary complex,thus providing a potential biomarker and therapeutic target for UM.