Jiang Xianjie, Peng Mingjing, Liu Qiang, Peng Qiu, Oyang Linda, Li Shizhen, Xu Xuemeng, Shen Mengzhou, Wang Jiewen, Li Haofan, Wu Nayiyuan, Tan Shiming, Lin Jinguan, Xia Longzheng, Tang Yanyan, Luo Xia, Liao Qianjin, Zhou Yujuan
Hunan Key Laboratory of Cancer Metabolism, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, 283 Tongzipo Road, Changsha, Hunan, 410013, China.
Hunan Engineering Research Center of Tumor organoids Technology and application, Public Service Platform of Tumor organoids Technology, 283 Tongzipo Road, Changsha, Hunan, 410013, China.
Mol Cancer. 2024 Jul 31;23(1):151. doi: 10.1186/s12943-024-02052-5.
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.
结直肠癌（CRC）是全球第二常见的恶性肿瘤，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，在肿瘤发展中起重要作用。然而，环状RNA在结直肠癌中的作用尚不清楚。
使用生物信息学分析在结直肠癌环状RNA微阵列中筛选环状RNA hsa_circ_0000467，并通过原位杂交确定hsa_circ_0000467在结直肠癌组织中的表达。评估hsa_circ_0000467表达水平与结直肠癌患者临床特征之间的关联。然后，通过CCK8测定、EdU测定、平板集落形成测定、伤口愈合测定和Transwell测定在体外以及在结直肠癌小鼠模型中体内评估hsa_circ_0000467在结直肠癌生长和转移中的作用。进行蛋白质组学分析和蛋白质印迹以研究hsa_circ_0000467对c-Myc信号通路的影响。进行多核糖体谱分析、RT-qPCR和双荧光素酶报告基因测定以确定hsa_circ_0000467对c-Myc翻译的影响。进行RNA下拉、RNA免疫沉淀（RIP）和免疫荧光染色以评估hsa_circ_0000467对eIF4A3分布的影响。
在本研究中，我们发现环状RNA hsa_circ_0000467在结直肠癌中高表达，并且与结直肠癌患者的不良预后显著相关。体外和体内实验表明，hsa_circ_0000467促进结直肠癌细胞的生长和转移。机制上，hsa_circ_0000467与eIF4A3结合以抑制其核转位。此外，它还可以作为支架分子，在细胞质中与eIF4A3和c-Myc mRNA结合形成复合物，从而促进c-Myc的翻译。反过来，c-Myc上调其下游靶点，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-钙黏蛋白，最终促进结直肠癌的生长和转移。
我们的研究结果表明，hsa_circRNA_0000467通过促进eIF4A3介导的c-Myc翻译在结直肠癌进展中起作用。本研究为结直肠癌的诊断和治疗提供了理论基础和分子靶点。
