Duan Shuyin, Yu Songcheng, Yuan Teng, Yao Sanqiao, Zhang Lin
Key Laboratory of Birth Regulation and Control Technology of National Health Commission of China, Shandong Maternal and Child Health Care Hospital, Jinan, China.
School of Public Health, Zhengzhou University, Zhengzhou, China.
Front Oncol. 2019 Aug 23;9:808. doi: 10.3389/fonc.2019.00808. eCollection 2019.
Elevated expression of let-7a-5p contributes to suppression of lung cancer, in which let-7a-5p, as exosome cargo, can be transported from macrophages to lung cancer cells, yet the role of let-7a-5p remains unclear. Utilizing bioinformatics methods and cellular experiments, this study was designed and conducted to identify let-7a-5p regulatory network in lung cancer. Bioinformatics analysis and Kaplan-Meier survival analysis revealed that let-7a-5p could directly target BCL2L1, and aberrant expression of let-7a-5p affects the survival of lung cancer patients, which was confirmed in A549 lung cancer cells using luciferase reporter assay. Moreover, let-7a-5p inhibited BCL2L1 expression and suppressed lung cancer cell proliferation, migration, and invasion. Functionally, overexpression of let-7a-5p promoted both autophagy and cell death in A549 lung cancer cells through PI3Kγ signaling pathway, whereas the apoptosis and pyroptosis of A549 lung cancer cells were unaffected. Furthermore, aberrant expression of BCL2L1 significantly altered the expression of lung cancer biomarkers such as MYC, EGFR, and Vimentin. To sum up, these data demonstrate that exogenous let-7a-5p induces A549 lung cancer cell death through BCL2L1-mediated PI3Kγ signaling pathway, which may be a useful target for lung cancer treatment.
let-7a-5p的高表达有助于抑制肺癌，其中let-7a-5p作为外泌体货物可从巨噬细胞转运至肺癌细胞，但其作用仍不清楚。本研究利用生物信息学方法和细胞实验，旨在识别肺癌中let-7a-5p的调控网络。生物信息学分析和Kaplan-Meier生存分析显示，let-7a-5p可直接靶向BCL2L1，且let-7a-5p的异常表达影响肺癌患者的生存，这在A549肺癌细胞中通过荧光素酶报告基因检测得到证实。此外，let-7a-5p抑制BCL2L1表达并抑制肺癌细胞的增殖、迁移和侵袭。在功能上，let-7a-5p的过表达通过PI3Kγ信号通路促进A549肺癌细胞的自噬和细胞死亡，而A549肺癌细胞的凋亡和焦亡未受影响。此外，BCL2L1的异常表达显著改变了肺癌生物标志物如MYC、EGFR和波形蛋白的表达。综上所述，这些数据表明外源性let-7a-5p通过BCL2L1介导的PI3Kγ信号通路诱导A549肺癌细胞死亡，这可能是肺癌治疗的一个有用靶点。
