Xu Muge, Gong Jiening
School of Chinese Medicine, School of Integrated Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing 210023, China.
J Oncol. 2022 Aug 16;2022:2524649. doi: 10.1155/2022/2524649. eCollection 2022.
Growing studies have implicated the association of ubiquitination-related genes (UbRGs) with the cancer progression and the long-term survival of patients. However, the prognostic values of UbRGs in lung adenocarcinoma (LUAD) have not been investigated. Our study aimed to establish a ubiquitination-related model for prognosis prediction and internal mechanism investigation. The transcriptome expression profiles and corresponding clinical information of LUAD were obtained from TCGA and GEO datasets. Differentially expressed genes (DEGs) were screened between LUAD specimens and nontumor specimens. Kaplan-Meier analysis and univariate assays were carried out on DEGs to preliminarily screen survival-related UbRGs. Then, the LASSO Cox regression model was applied to develop a multigene signature, which was then demonstrated in two GEO datasets by the use of Kaplan-Meier, ROC, and Cox analyses. We estimated the immune cell infiltration in tumor microenvironment via CIBERSORT and immunotherapy response through the TIDE algorithm. In this study, a total of 71 ubiquitination-related DEGs were identified. Nine UbRGs, including TUBA4A, TRIM2, PLK1, ARRB1, TRIM58, PLK1, ARRB1, CCNB1, TRIM6, PTTG1, and CCT2, were included to establish a risk model, which was validated in TCGA and GEO datasets. The multivariate assays demonstrated that the 9-UbRGs signature was a robust independent prognostic factor in the overall survival of LUAD patients. The abundance of CD8 T cells, activated CD4 T memory cells, resting NK cells and macrophages was higher in the high-risk group, and the TMB of high-risk group was statistically higher than the low-risk group. Multiple drugs approved by FAD, targeting UbRGs, were available for the treatment of LUAD. Overall, we identified a nine ubiquitination-related gene signature, and the signature may be applied to be a potential biomarker for CD8 T cells response and clinical responses to immune checkpoint inhibitors for LUAD.
越来越多的研究表明泛素化相关基因（UbRGs）与癌症进展及患者长期生存有关。然而，UbRGs在肺腺癌（LUAD）中的预后价值尚未得到研究。我们的研究旨在建立一个用于预后预测和内在机制研究的泛素化相关模型。从TCGA和GEO数据集中获取LUAD的转录组表达谱及相应临床信息。在LUAD标本和非肿瘤标本之间筛选差异表达基因（DEGs）。对DEGs进行Kaplan-Meier分析和单变量分析，以初步筛选与生存相关的UbRGs。然后，应用LASSO Cox回归模型构建多基因特征，随后通过Kaplan-Meier、ROC和Cox分析在两个GEO数据集中进行验证。我们通过CIBERSORT评估肿瘤微环境中的免疫细胞浸润，并通过TIDE算法评估免疫治疗反应。在本研究中，共鉴定出71个泛素化相关DEGs。包括TUBA4A、TRIM2、PLK1、ARRB1、TRIM58、PLK1、ARRB1、CCNB1、TRIM6、PTTG1和CCT2在内的9个UbRGs被纳入建立风险模型，并在TCGA和GEO数据集中进行了验证。多变量分析表明，9-UbRGs特征是LUAD患者总生存的一个强大独立预后因素。高风险组中CD8 T细胞、活化的CD4 T记忆细胞、静息NK细胞和巨噬细胞的丰度较高，且高风险组的肿瘤突变负荷在统计学上高于低风险组。美国食品药品监督管理局（FAD）批准的多种靶向UbRGs的药物可用于治疗LUAD。总体而言，我们鉴定出一个由9个泛素化相关基因组成的特征，该特征可能作为LUAD中CD8 T细胞反应和免疫检查点抑制剂临床反应的潜在生物标志物。
