PDF(Pubmed)
Abstract：
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.
摘要：
许多研究已经描述了环状RNA（circularRNAs，circRNAs）作为调节因子在多种癌症进展中的关键作用。然而,circRNAs的生物学功能及其在葡萄膜黑色素瘤（UM）进展中的潜在分子机制仍然是个谜。在这项研究中,我们发现了一种新的circRNA,circ_0053943，通过UM微阵列数据的再分析和定量RT-PCR。发现Circ_0053943在UM中上调,并在体外和体内设置中促进UM细胞的增殖和转移能力。机械上,观察到circ_0053943与胰岛素样生长因子2mRNA结合蛋白3（IGF2BP3）的KH1和KH2结构域结合，从而通过稳定其靶mRNA来增强IGF2BP3的功能。RNA测序测定鉴定表皮生长因子受体(EGFR)为转录水平的circ_0053943和IGF2BP3的靶基因。拯救实验表明，circ_0053943通过稳定EGFRmRNA和调节下游丝裂原活化蛋白激酶/细胞外信号调节激酶（MAPK/ERK）信号通路发挥其生物学功能。总的来说，circ_0053943可能通过稳定EGFRmRNA并通过形成circ_0053943/IGF2BP3/EGFRRNA-蛋白三元复合物激活MAPK/ERK信号通路来促进UM进展,从而为UM提供潜在的生物标志物和治疗靶点。
