Multiple lines of evidence have demonstrated that circular RNAs (circRNAs) play oncogenic or tumor-suppressive roles in various human cancers. Nevertheless, the biological functions of circRNAs in small cell lung cancer (SCLC) are still elusive. CircVAPA (annotated as hsa_circ_0006990) was identified by mining the circRNA profiling dataset of six paired SCLC tissues and the RNA-seq data of serum samples from 36 SCLC patients and 118 healthy controls. The circVAPA expression level was evaluated using quantitative real-time PCR in SCLC cells and tissues. Cell viability, colony formation, cell cycle and apoptosis analysis assays and in vivo tumorigenesis were used to reveal the biological roles of circVAPA. The underlying mechanism of circVAPA was investigated by Western blot, RNA pulldown, RNA immunoprecipitation, dual-luciferase reporter assay and rescue experiments. We revealed that circVAPA, derived from exons 2-4 of the vesicle-associated membrane protein-associated protein A (VAPA) gene, exhibited higher expression levels in SCLC cell lines, clinical tissues, and serum from SCLC patients than the controls, and facilitated SCLC progression in vitro and in vivo. Mechanistically, circVAPA activated the phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT) signaling pathway by modulating the miR-377-3p and miR-494-3p/insulin-like growth factor 1 receptor (IGF1R) axis to accelerate SCLC progression. Furthermore, circVAPA depletion markedly enhanced the inhibitory effects of BMS-536924, an IGF1R kinase inhibitor in cellular and xenograft mouse models. CircVAPA promotes SCLC progression via the miR-377-3p and miR-494-3p/IGF1R/AKT axis. We hope to develop clinical protocols of combinations of circVAPA inhibition and BMS-536924 addition for treating SCLC with circVAPA upregulation.

中文翻译：

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CircVAPA 通过调节 miR-377-3p 和 miR-494-3p/IGF1R/AKT 轴促进小细胞肺癌进展

多项证据表明，环状 RNA (circRNA) 在各种人类癌症中发挥致癌或肿瘤抑制作用。尽管如此，circRNA在小细胞肺癌（SCLC）中的生物学功能仍然难以捉摸。CircVAPA（注释为 hsa_circ_0006990）是通过挖掘六对 SCLC 组织的 circRNA 分析数据集和来自 36 名 SCLC 患者和 118 名健康对照者的血清样本的 RNA-seq 数据来确定的。在 SCLC 细胞和组织中使用定量实时 PCR 评估 circVAPA 表达水平。细胞活力、集落形成、细胞周期和细胞凋亡分析测定以及体内肿瘤发生被用来揭示 circVAPA 的生物学作用。circVAPA的潜在机制通过Western blot、RNA pulldown、RNA免疫沉淀、双荧光素酶报告基因检测和救援实验。我们发现，源自囊泡相关膜蛋白相关蛋白 A (VAPA) 基因的外显子 2-4 的 circVAPA 在 SCLC 细胞系、临床组织和 SCLC 患者血清中的表达水平高于对照组，并促进SCLC 在体外和体内的进展。机制上，circVAPA 通过调节 miR-377-3p 和 miR-494-3p/胰岛素样生长因子 1 受体 (IGF1R) 轴激活磷酸肌醇 3-激酶 (PI3K)/蛋白激酶 B (AKT) 信号通路以加速 SCLC进展。此外，circVAPA 消耗显着增强了 BMS-536924（一种 IGF1R 激酶抑制剂）在细胞和异种移植小鼠模型中的抑制作用。CircVAPA 通过 miR-377-3p 和 miR-494-3p/IGF1R/AKT 轴促进 SCLC 进展。