Circular RNAs (circRNAs) have been documented to play crucial roles in the biology of various cancers. However, their investigation in melanoma is still at an early stage, particularly as a broader mechanism beyond acting as miRNA sponges needs to be explored. We report here that circFCHO2(hsa_circ_0002490), a circRNA encompassing exons 19 and 20 of the FCHO2 gene, exhibited a consistent overexpression in melanoma tissues. Furthermore, elevated circFCHO2 levels demonstrated a positive correlation with the malignant phenotype and poor prognosis among the 158 melanoma patients studied. Besides, we observed that heightened levels of circFCHO2 promoted melanoma cell proliferation, migration, and invasion in vitro, along with contributing to tumor growth in vivo. Furthermore, we found differences in the secondary structure of circFCHO2 compared to most other circular RNA structures. It has fewer miRNA binding sites, while it has more RNA binding protein binding sites. We therefore speculate that circFCHO2 may have a function of interacting with RNA binding proteins. Mechanistically, it was confirmed by fluorescence in situ hybridization (FISH), RNA-pull down, RNA immunoprecipitation (RIP), and western blotting assays that circFCHO2 interacts with dead end protein homolog 1 (DND1) and reverses the inhibition of the PI3K/AKT signaling pathway by binding to DND1. Our findings reveal that circFCHO2 drives melanoma progression by regulating the PI3K/AKT signaling pathway through direct binding to DND1 and may serve as a potential diagnostic biomarker and therapeutic target for the treatment of melanoma.

Graphical Abstract

Headlights: CircFCHO2 is highly expressed in melanoma. High circFCHO2 levels were positively correlated with poor prognosis in 158 melanoma patients. CircFCHO2 is involved in the regulation of the PI3K/AKT signalling pathway by binding to DND1. CircFCHO2 could serve as a potential biomarker and therapeutic target for the management of melanoma.

中文翻译：

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环状RNA circFCHO2(hsa_circ_0002490)通过直接结合DND1促进黑色素瘤增殖

环状 RNA (circRNA) 已被证明在各种癌症的生物学中发挥着至关重要的作用。然而，他们对黑色素瘤的研究仍处于早期阶段，特别是需要探索 miRNA 海绵以外的更广泛的机制。我们在此报告，circFCHO2（hsa_circ_0002490）是一种包含 FCHO2 基因外显子 19 和 20 的 circRNA，在黑色素瘤组织中表现出一致的过表达。此外，在所研究的 158 名黑色素瘤患者中，circFCHO2 水平升高与恶性表型和不良预后呈正相关。此外，我们观察到，circFCHO2水平升高可促进体外黑色素瘤细胞增殖、迁移和侵袭，同时促进体内肿瘤生长。此外，我们发现 circFCHO2 的二级结构与大多数其他环状 RNA 结构存在差异。它具有较少的 miRNA 结合位点，而具有较多的 RNA 结合蛋白结合位点。因此我们推测circFCHO2可能具有与RNA结合蛋白相互作用的功能。从机制上讲，通过荧光原位杂交 (FISH)、RNA 下拉、RNA 免疫沉淀 (RIP) 和蛋白质印迹测定证实 circFCHO2 与死端蛋白同源物 1 (DND1) 相互作用并逆转 PI3K/AKT 的抑制通过与 DND1 结合的信号通路。我们的研究结果表明，circFCHO2 通过直接结合 DND1 来调节 PI3K/AKT 信号通路，从而驱动黑色素瘤进展，并可能作为黑色素瘤治疗的潜在诊断生物标志物和治疗靶点。

图形概要

Headlights：CircFCHO2 在黑色素瘤中高度表达。在 158 名黑色素瘤患者中，高 circFCHO2 水平与不良预后呈正相关。 CircFCHO2 通过与 DND1 结合参与 PI3K/AKT 信号通路的调节。 CircFCHO2可以作为治疗黑色素瘤的潜在生物标志物和治疗靶点。