Circular RNAs (circRNAs) have been found to have significant impacts on bladder cancer (BC) progression through various mechanisms. In this study, we aimed to identify novel circRNAs that regulate the function of IGF2BP1, a key m6A reader, and explore the regulatory mechanisms and clinical significances in BC. Firstly, the clinical role of IGF2BP1 in BC was studied. Then, RNA immunoprecipitation sequencing (RIP-seq) analysis was performed to identify the circRNAs interacted with IGF2BP1 in BC cells. The overall biological roles of IGF2BP1 and the candidate circPTPRA were investigated in both BC cell lines and animal xenograft studies. Subsequently, we evaluated the regulation effects of circPTPRA on IGF2BP1 and screened out its target genes through RNA sequencing. Finally, we explored the underlying molecular mechanisms that circPTPRA might act as a blocker in recognition of m6A. We demonstrated that IGF2BP1 was predominantly binded with circPTPRA in the cytoplasm in BC cells. Ectopic expression of circPTPRA abolished the promotion of cell proliferation, migration and invasion of BC cells induced by IGF2BP1. Importantly, circPTPRA downregulated IGF2BP1-regulation of MYC and FSCN1 expression via interacting with IGF2BP1. Moreover, the recognition of m6A-modified RNAs mediated by IGF2BP1 was partly disturbed by circPTPRA through its interaction with KH domains of IGF2BP1. This study identifies exonic circular circPTPRA as a new tumor suppressor that inhibits cancer progression through endogenous blocking the recognition of IGF2BP1 to m6A-modified RNAs, indicating that circPTPRA may serve as an exploitable therapeutic target for patients with BC.

中文翻译：

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CircPTPRA 通过与 IGF2BP1 相互作用阻断 RNA N6-甲基腺苷的识别以抑制膀胱癌进展

已发现环状 RNA (circRNA) 通过各种机制对膀胱癌 (BC) 进展产生重大影响。在本研究中，我们旨在鉴定调节关键 m6A 阅读器 IGF2BP1 功能的新型 circRNA，并探索 BC 中的调节机制和临床意义。首先，研究了IGF2BP1在BC中的临床作用。然后，进行 RNA 免疫沉淀测序 (RIP-seq) 分析以鉴定 BC 细胞中与 IGF2BP1 相互作用的 circRNA。在 BC 细胞系和动物异种移植研究中研究了 IGF2BP1 和候选 circPTPRA 的整体生物学作用。随后，我们评估了circPTPRA对IGF2BP1的调控作用，并通过RNA测序筛选出其靶基因。最后，我们探索了 circPTPRA 可能作为识别 m6A 的阻断剂的潜在分子机制。我们证明 IGF2BP1 在 BC 细胞的细胞质中主要与 circPTPRA 结合。circPTPRA的异位表达消除了IGF2BP1诱导的BC细胞对细胞增殖、迁移和侵袭的促进作用。重要的是，circPTPRA 通过与 IGF2BP1 相互作用下调了 IGF2BP1 对 MYC 和 FSCN1 表达的调节。此外，circPTPRA 通过与 IGF2BP1 的 KH 结构域相互作用，部分干扰了对 IGF2BP1 介导的 m6A 修饰 RNA 的识别。这项研究将外显子环状 circPTPRA 鉴定为一种新的肿瘤抑制因子，通过内源性阻断 IGF2BP1 对 m6A 修饰的 RNA 的识别来抑制癌症进展，