Department of Oncology, Beijing Chao‑Yang Hospital, Capital Medical University, Beijing 100020, P.R. China.
Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, P.R. China.
Int J Oncol. 2019 May;54(5):1821-1832. doi: 10.3892/ijo.2019.4738. Epub 2019 Mar 1.
Lung adenocarcinoma (LA) is the most commonly occurring histological type of non‑small cell lung cancer. Diagnosis and treatment of LA remain a major clinical challenge. In the present study, to identify early LA biomarkers, extracellular vesicles (EVs) were separated from the plasma samples from 153 patients with LA and 75 healthy controls. microRNA (miRNA) expression profiling was performed at the screening stage (5 patients with LA vs. 5 controls), followed by verification at the validation stage (40 patients with LA vs. 20 controls) using reverse transcription‑quantitative polymerase chain reaction (RT‑qPCR). The four disordered miRNAs (miR‑505‑5p, miR‑486‑3p, miR‑486‑3p and miR‑382‑3p) identified in the plasma EVs were further evaluated at the testing stage (108 patients with LA vs. 50 controls) by RT‑qPCR. It was revealed that miR‑505‑5p was upregulated, whereas miR‑382‑3p was downregulated, in the EVs from patients with LA. Furthermore, miR‑505‑5p was also upregulated in tumor tissues, compared with adjacent non‑tumor control tissues. Subsequently, the direct targets of miR‑505‑5p were predicted using bioinformatics analyses, and verified by luciferase assay and immunoblotting. The present study determined that miR‑505‑5p functions as an oncogene, promoting lung cancer cell proliferation and inhibiting cancer cell apoptosis via the targeting of tumor protein P53‑regulated apoptosis‑inducing protein 1 (TP53AIP1). Finally, it was confirmed that miR‑505‑5p in plasma EVs could be delivered to lung cancer cells, inhibiting cell apoptosis and promoting cell proliferation by targeting TP53AIP1. In conclusion, the present study indicated that miRNA‑505‑5p functions as an oncogene that may be used as a novel biomarker for the diagnosis and treatment of LA.
肺腺癌(LA)是最常见的非小细胞肺癌组织学类型。LA 的诊断和治疗仍然是一个主要的临床挑战。在本研究中,为了鉴定早期 LA 的生物标志物,从 153 例 LA 患者和 75 例健康对照者的血浆样本中分离出外泌体(EVs)。在筛选阶段(5 例 LA 患者与 5 例对照者)进行 microRNA(miRNA)表达谱分析,随后在验证阶段(40 例 LA 患者与 20 例对照者)使用逆转录-定量聚合酶链反应(RT-qPCR)进行验证。在血浆 EVs 中鉴定出的四个失调 miRNA(miR-505-5p、miR-486-3p、miR-486-3p 和 miR-382-3p)在测试阶段(108 例 LA 患者与 50 例对照者)通过 RT-qPCR 进一步评估。结果显示,LA 患者的 EV 中 miR-505-5p 上调,而 miR-382-3p 下调。此外,与相邻非肿瘤对照组织相比,miR-505-5p 在肿瘤组织中也上调。随后,通过生物信息学分析预测 miR-505-5p 的直接靶标,并通过荧光素酶测定和免疫印迹进行验证。本研究确定 miR-505-5p 作为一种致癌基因,通过靶向肿瘤蛋白 P53 调节凋亡诱导蛋白 1(TP53AIP1)促进肺癌细胞增殖并抑制癌细胞凋亡。最后,证实血浆 EVs 中的 miR-505-5p 可通过靶向 TP53AIP1 递送至肺癌细胞,抑制细胞凋亡并促进细胞增殖。总之,本研究表明 miR-505-5p 作为一种致癌基因发挥作用,可作为 LA 诊断和治疗的新型生物标志物。