Song Jing, Liu Jia, Lv Dekang, Meng Xuan, Li Xiaodong
Department of Respiratory Medicine, Qinzhou First People's Hospital, The Tenth Affiliated Hospital of Guangxi Medical University, Qinzhou, China.
Department of Gynecology, Cancer Hospital of China Medical University, Dalian, China.
Front Genet. 2021 Oct 19;12:767259. doi: 10.3389/fgene.2021.767259. eCollection 2021.
Alternative splicing (AS) is significantly related to tumor development as well as a patient's clinical characteristics. This study was designed to systematically analyze the survival-associated AS signatures in Lung adenocarcinoma (LUAD). Among 30,735 AS events in 9,635 genes, we found that there were 1,429 AS in 1,125 genes which were conspicuously related to the overall survival of LUAD patients. Then, according to the seven types of AS events, we established AS signatures and constructed a new combined prognostic model. The Kaplan-Meier curve results showed that seven types of AS signatures and the combined prognostic model could divide patients into distinct prognoses. The ROC curve shows that all eight AS signatures had powerful predictive properties with different AUCs ranging from 0.708 to 0.849. Additionally, the elevated risk scores were positively related to higher TNM stage and metastasis. Interestingly, AS events and splicing factors (SFs) network shed light on a meaningful connection between prognostic AS genes and corresponding SFs. Moreover, we found that the combined prognostic model signature has a higher predictive ability than the mRNA signature. Furthermore, tumors at high risk might evade immune recognition by decreasing the expression of antigen presentation genes. Finally, we predicted the three most significant small molecule drugs to inhibit LUAD. Among them, NVP-AUY922 had the lowest IC50 value and might become a potential drug to prolong a patient's survival. In conclusion, our study established a potential prognostic signature for LUAD patients, revealed a splicing network between AS and SFs and possible immune escape mechanism, and provided several small-molecule drugs to inhibit tumorigenesis.
可变剪接（AS）与肿瘤发展以及患者的临床特征显著相关。本研究旨在系统分析肺腺癌（LUAD）中与生存相关的AS特征。在9635个基因中的30735个AS事件中，我们发现1125个基因中的1429个AS与LUAD患者的总生存显著相关。然后，根据七种AS事件类型，我们建立了AS特征并构建了一个新的联合预后模型。Kaplan-Meier曲线结果显示，七种AS特征和联合预后模型可将患者分为不同的预后组。ROC曲线表明，所有八个AS特征都具有强大的预测性能，不同的AUC范围为0.708至0.849。此外，风险评分升高与更高的TNM分期和转移呈正相关。有趣的是，AS事件和剪接因子（SFs）网络揭示了预后AS基因与相应SFs之间的有意义联系。此外，我们发现联合预后模型特征比mRNA特征具有更高的预测能力。此外，高危肿瘤可能通过降低抗原呈递基因的表达来逃避免疫识别。最后，我们预测了三种最有效的抑制LUAD的小分子药物。其中，NVP-AUY922的IC50值最低，可能成为延长患者生存期的潜在药物。总之，我们的研究为LUAD患者建立了一个潜在的预后特征，揭示了AS和SFs之间的剪接网络以及可能的免疫逃逸机制，并提供了几种抑制肿瘤发生的小分子药物。
