Circular RNAs (circRNAs) play important roles in cancer development and progression. The purpose of this study is to identify aberrantly expressed circRNAs in gastric cancer (GC), unravel their roles in GC progression, and provide new targets for GC diagnosis and therapy. Bioinformatic analyses were performed to identify the aberrantly expression of hsa_circ_0061137 (termed as circDIDO1) in GC. Gain- and loss-of-function studies were performed to examine the biological roles of circDIDO1 in GC progression. Tagged RNA affinity purification, mass spectrometry, immunofluorescence, co-immunoprecipitation, and Western blot were used to identify circRNA-interacting and circRNA-encoded proteins. RNA sequencing, qRT-PCR, and Western blot were performed to analyze circRNA-regulated downstream target genes and signaling pathways. Mouse tumor models were used to analyze the effects of circDIDO1 on GC growth and metastasis. CircDIDO1 was transcribed from human DIDO1 (death-inducer obliterator 1) gene and formed by back-splicing of exons 2–6 of the linear transcript. circDIDO1 was down-regulated in GC tissues and its low levels were associated with larger tumor size, distal metastasis, and poor prognosis. CircDIDO1 overexpression inhibited while knockdown promoted GC cell proliferation, migration and invasion. CircDIDO1 overexpression suppressed GC growth and metastasis in mouse tumor models. Mechanistically, circDIDO1 encoded a novel 529aa protein that directly interacted with poly ADP-ribose polymerase 1 (PARP1) and inhibited its activity. CircDIDO1 also specifically bound to peroxiredoxin 2 (PRDX2) and promoted RBX1-mediated ubiquitination and degradation of PRDX2, which led to the inactivation of its downstream signaling pathways. CircDIDO1 is a new circRNA that has tumor suppressor function in GC and it may serve as a potential prognostic biomarker and therapeutic target for GC.

中文翻译：

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CircDIDO1通过编码一种新型DIDO1-529aa蛋白和调节PRDX2蛋白稳定性来抑制胃癌进展

环状 RNA (circRNA) 在癌症的发展和进展中发挥着重要作用。本研究的目的是鉴定胃癌（GC）中异常表达的circRNA，揭示它们在胃癌进展中的作用，并为胃癌的诊断和治疗提供新的靶点。进行生物信息学分析以鉴定 hsa_circ_0061137（称为 circDIDO1）在 GC 中的异常表达。进行了功能增益和功能丧失研究以检查 circDIDO1 在 GC 进展中的生物学作用。标记 RNA 亲和纯化、质谱、免疫荧光、共免疫沉淀和蛋白质印迹用于鉴定 circRNA 相互作用和 circRNA 编码的蛋白质。进行 RNA 测序、qRT-PCR 和蛋白质印迹以分析 circRNA 调节的下游靶基因和信号通路。小鼠肿瘤模型用于分析circDIDO1对GC生长和转移的影响。CircDIDO1 由人类 DIDO1（死亡诱导闭塞蛋白 1）基因转录而成，由线性转录本的外显子 2-6 反向剪接形成。circDIDO1 在 GC 组织中下调，其低水平与较大的肿瘤大小、远端转移和预后不良有关。CircDIDO1 过表达抑制，而敲低促进 GC 细胞增殖、迁移和侵袭。CircDIDO1 过表达抑制小鼠肿瘤模型中的 GC 生长和转移。从机制上讲，circDIDO1 编码了一种新的 529aa 蛋白，该蛋白直接与聚 ADP-核糖聚合酶 1 (PARP1) 相互作用并抑制其活性。CircDIDO1 还与过氧化还原蛋白 2 (PRDX2) 特异性结合并促进 RBX1 介导的 PRDX2 泛素化和降解，这导致其下游信号通路失活。CircDIDO1 是一种新的 circRNA，在 GC 中具有抑癌功能，可作为潜在的 GC 预后生物标志物和治疗靶点。