Circ_0053943 complexed with IGF2BP3 drives uveal melanoma progression via regulating N6-methyladenosine modification of Epidermal growth factor receptor.

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.