Circular RNA hsa_circ_0000467 promotes colorectal cancer progression by promoting eIF4A3-mediated c-Myc translation

IF 27.7 1区医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Molecular Cancer Pub Date : 2024-07-31 DOI:10.1186/s12943-024-02052-5

Xianjie Jiang, Mingjing Peng, Qiang Liu, Qiu Peng, Linda Oyang, Shizhen Li, Xuemeng Xu, Mengzhou Shen, Jiewen Wang, Haofan Li, Nayiyuan Wu, Shiming Tan, Jinguan Lin, Longzheng Xia, Yanyan Tang, Xia Luo, Qianjin Liao, Yujuan Zhou

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Abstract

Colorectal cancer (CRC) is the second most common malignant tumor worldwide, and its incidence rate increases annually. Early diagnosis and treatment are crucial for improving the prognosis of patients with colorectal cancer. Circular RNAs are noncoding RNAs with a closed-loop structure that play a significant role in tumor development. However, the role of circular RNAs in CRC is poorly understood. The circular RNA hsa_circ_0000467 was screened in CRC circRNA microarrays using a bioinformatics analysis, and the expression of hsa_circ_0000467 in CRC tissues was determined by in situ hybridization. The associations between the expression level of hsa_circ_0000467 and the clinical characteristics of CRC patients were evaluated. Then, the role of hsa_circ_0000467 in CRC growth and metastasis was assessed by CCK8 assay, EdU assay, plate colony formation assay, wound healing assay, and Transwell assay in vitro and in a mouse model of CRC in vivo. Proteomic analysis and western blotting were performed to investigate the effect of hsa_circ_0000467 on c-Myc signaling. Polysome profiling, RT‒qPCR and dual-luciferase reporter assays were performed to determine the effect of hsa_circ_0000467 on c-Myc translation. RNA pull-down, RNA immunoprecipitation (RIP) and immunofluorescence staining were performed to assess the effect of hsa_circ_0000467 on eIF4A3 distribution. In this study, we found that the circular RNA hsa_circ_0000467 is highly expressed in colorectal cancer and is significantly correlated with poor prognosis in CRC patients. In vitro and in vivo experiments revealed that hsa_circ_0000467 promotes the growth and metastasis of colorectal cancer cells. Mechanistically, hsa_circ_0000467 binds eIF4A3 to suppress its nuclear translocation. In addition, it can also act as a scaffold molecule that binds eIF4A3 and c-Myc mRNA to form complexes in the cytoplasm, thereby promoting the translation of c-Myc. In turn, c-Myc upregulates its downstream targets, including the cell cycle-related factors cyclin D2 and CDK4 and the tight junction-related factor ZEB1, and downregulates E-cadherin, which ultimately promotes the growth and metastasis of CRC. Our findings revealed that hsa_circRNA_0000467 plays a role in the progression of CRC by promoting eIF4A3-mediated c-Myc translation. This study provides a theoretical basis and molecular target for the diagnosis and treatment of CRC.

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环状 RNA hsa_circ_0000467 通过促进 eIF4A3 介导的 c-Myc 翻译来推动结直肠癌的进展

结直肠癌（CRC）是全球第二大常见恶性肿瘤，其发病率逐年上升。早期诊断和治疗对于改善结直肠癌患者的预后至关重要。环状 RNA 是具有闭环结构的非编码 RNA，在肿瘤发生发展过程中发挥着重要作用。然而，人们对环状 RNA 在 CRC 中的作用还知之甚少。通过生物信息学分析，在 CRC circRNA 微阵列中筛选出了环状 RNA hsa_circ_0000467，并通过原位杂交测定了 hsa_circ_0000467 在 CRC 组织中的表达。评估了 hsa_circ_0000467 的表达水平与 CRC 患者临床特征之间的关联。然后，通过 CCK8 试验、EdU 试验、平板集落形成试验、伤口愈合试验和 Transwell 试验，在体外和小鼠 CRC 模型中评估了 hsa_circ_0000467 在 CRC 生长和转移中的作用。为了研究 hsa_circ_0000467 对 c-Myc 信号转导的影响，进行了蛋白质组分析和 Western 印迹。为了确定 hsa_circ_0000467 对 c-Myc 翻译的影响，进行了多聚体分析、RT-qPCR 和双荧光素酶报告实验。为了评估 hsa_circ_0000467 对 eIF4A3 分布的影响，我们进行了 RNA 拉取、RNA 免疫沉淀（RIP）和免疫荧光染色。在这项研究中，我们发现环状 RNA hsa_circ_0000467 在结直肠癌中高表达，并与 CRC 患者的不良预后显著相关。体外和体内实验显示，hsa_circ_0000467 能促进结直肠癌细胞的生长和转移。从机理上讲，hsa_circ_0000467 与 eIF4A3 结合，抑制其核转位。此外，它还可以作为支架分子，与 eIF4A3 和 c-Myc mRNA 结合，在细胞质中形成复合物，从而促进 c-Myc 的翻译。反过来，c-Myc 会上调其下游靶标，包括细胞周期相关因子细胞周期蛋白 D2 和 CDK4 以及紧密连接相关因子 ZEB1，并下调 E-cadherin，最终促进 CRC 的生长和转移。我们的研究结果表明，hsa_circRNA_0000467通过促进eIF4A3介导的c-Myc翻译，在CRC的进展过程中发挥作用。这项研究为诊断和治疗 CRC 提供了理论依据和分子靶点。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Molecular Cancer 医学-生化与分子生物学

CiteScore

54.90

自引率

2.70%

发文量

224

审稿时长

2 months

期刊介绍： Molecular Cancer is a platform that encourages the exchange of ideas and discoveries in the field of cancer research, particularly focusing on the molecular aspects. Our goal is to facilitate discussions and provide insights into various areas of cancer and related biomedical science. We welcome articles from basic, translational, and clinical research that contribute to the advancement of understanding, prevention, diagnosis, and treatment of cancer. The scope of topics covered in Molecular Cancer is diverse and inclusive. These include, but are not limited to, cell and tumor biology, angiogenesis, utilizing animal models, understanding metastasis, exploring cancer antigens and the immune response, investigating cellular signaling and molecular biology, examining epidemiology, genetic and molecular profiling of cancer, identifying molecular targets, studying cancer stem cells, exploring DNA damage and repair mechanisms, analyzing cell cycle regulation, investigating apoptosis, exploring molecular virology, and evaluating vaccine and antibody-based cancer therapies. Molecular Cancer serves as an important platform for sharing exciting discoveries in cancer-related research. It offers an unparalleled opportunity to communicate information to both specialists and the general public. The online presence of Molecular Cancer enables immediate publication of accepted articles and facilitates the presentation of large datasets and supplementary information. This ensures that new research is efficiently and rapidly disseminated to the scientific community.