Department of Thoracic Surgery, Jiangsu Key Laboratory of Molecular and Translational Cancer Research, The Affiliated Cancer Hospital of Nanjing Medical University, Jiangsu Cancer Hospital, Jiangsu Institute of Cancer Research, Nanjing, China.
Department of Oncology, Department of Geriatric Lung Cancer Laboratory, The Affiliated Geriatric Hospital of Nanjing Medical University, Nanjing, China.
Cancer Sci. 2019 Sep;110(9):2960-2972. doi: 10.1111/cas.14131. Epub 2019 Aug 14.
In recent years, circular RNAs (circRNAs) have been revealed to have important roles in carcinogenesis. Metastasis is the leading cause of lung adenocarcinoma (LUAC) death. However, the contributions of circRNA to the metastasis of LUAC remain largely unknown. Based on circBase data and our biobank tissues, we identified circCRIM1 (a circRNA derived from exons 2, 3 and 4 of the CRIM1 gene, hsa_circ_0002346) as having a significantly decreased expression in LUAC samples compared with matched normal control samples. Both in vivo and in vitro experiments revealed that circCRIM1 suppresses the invasion and metastasis of LUAC. In vitro precipitation of circRNAs, luciferase reporter assay, and biotin-coupled microRNA capture were carried out to investigate the Ago2-dependent interaction of circCRIM1 and microRNA (miR)-93/miR-182. Mechanistically, we found that circCRIM1 could promote the expression of leukemia inhibitory factor receptor, a well-known tumor suppressor, by sponging miR-93 and miR-182. In the clinical and pathological analyses, the downregulation of circCRIM1 in LUAC was significantly correlated with lymphatic metastasis and TNM stage, which served as an independent risk factor for the overall survival of patients with LUAC. Our study showed that circCRIM1 inhibits the invasion and metastasis of lung adenocarcinoma cancer cells, which makes it a potential therapeutic target.
近年来，环状 RNA（circRNAs）被发现在癌症发生中具有重要作用。转移是肺腺癌（LUAC）死亡的主要原因。然而，circRNA 对 LUAC 转移的贡献在很大程度上仍然未知。基于 circBase 数据和我们的生物银行组织，我们确定 circCRIM1（一种源自 CRIM1 基因外显子 2、3 和 4 的 circRNA，hsa_circ_0002346）在 LUAC 样本中的表达明显低于匹配的正常对照样本。体内和体外实验均表明 circCRIM1 抑制 LUAC 的侵袭和转移。进行了 circRNAs 的体外沉淀、荧光素酶报告基因检测和生物素偶联 microRNA 捕获实验，以研究 circCRIM1 和 microRNA（miR）-93/miR-182 之间的 Ago2 依赖性相互作用。在机制上，我们发现 circCRIM1 可以通过海绵吸附 miR-93 和 miR-182 来促进白血病抑制因子受体的表达，白血病抑制因子受体是一种已知的肿瘤抑制因子。在临床和病理分析中，LUAC 中 circCRIM1 的下调与淋巴转移和 TNM 分期显著相关，这是 LUAC 患者总生存期的独立危险因素。我们的研究表明，circCRIM1 抑制肺腺癌癌细胞的侵袭和转移，使其成为一种潜在的治疗靶点。
