肺腺癌(LUAD)是世界上最普遍的癌症之一,其发病率逐年上升。越来越多的证据表明,内质网应激在癌细胞中高度激活,并在调节癌细胞的命运中起关键作用。然而,内质网应激在肺腺癌发生发展中的作用及机制尚不清楚。在这项研究中,我们利用内质网应激相关基因建立了预测LUAD患者总生存期的预后模型,并筛选出潜在的小分子化合物,这可以帮助临床医生做出准确的决定,并更好地治疗LUAD患者。首先,我们从分子特征数据库(MSigDB)下载了419个内质网应激相关基因(ERSRGs)。其次,我们从癌症基因组图谱(TCGA)数据库中获得了59个正常样本和535个肺腺癌样本的转录组分析和相应的临床数据.接下来,我们使用DESeq2软件包来鉴定与内质网应激相关的差异表达基因。我们做了单变量考克斯,最小绝对收缩和选择运算符(LASSO),多因素Cox回归分析建立基于ERSRGs的LUAD患者预后模型。然后,我们对内质网应激相关基因(ERSRG)评分和肺腺癌的一些临床特征进行了单因素和多因素独立预后分析.此外,我们开发了一个临床适用的列线图,用于预测LUAD患者的生存率超过1,三,还有五年.此外,我们进行了药物敏感性分析,以鉴定用于LUAD治疗的新型小分子化合物.最后,我们检查了肿瘤微环境(TME)和免疫细胞浸润分析,以探索免疫和癌细胞之间的相互作用。通过使用DESeq2软件包鉴定了142个差异表达的ERSRG。在进行单变量Cox回归后,基于7个差异表达的ERSRGs建立了预后模型,LASSO回归,和多变量Cox回归分析。根据单因素和多因素独立预后分析的结果,我们发现ERSRG评分可以作为独立的预后指标.使用Kaplan-Meier曲线,我们发现,在训练集和测试集中,低危患者的生存概率均高于高危患者.绘制了一个列线图来预测1-,3-,和5年生存概率。校准曲线解释了用于预测生存的模型的良好性能。苯乙双胍,OSU-03012,GSK-650394和KIN001-135被确定为最有可能为临床医生提供有关LUAD患者治疗的重要信息的药物。基于7个差异表达的ERSRGs(PDX1、IGFBP1、DDIT4、PPP1R3G、CFTR,DERL3和NUPR1),能有效预测LUAD患者的预后,为临床医生帮助LUAD患者制定更好的治疗策略提供参考。基于4个小分子化合物(苯乙双胍,OSU-03012,GSK-650394和KIN001-135)我们发现,靶向内质网应激相关基因也可能是LUAD患者的治疗方法.
Lung adenocarcinoma (LUAD) is one of the most universal types of cancer all over the world and its morbidity continues to rise year by year. Growing evidence has demonstrated that endoplasmic reticulum stress is highly activated in cancer cells and plays a key role in regulating the fate of cancer cells. However, the role and mechanism of endoplasmic reticulum stress in lung adenocarcinoma genesis and development remains unclear. In this research, we developed a prognostic model to predict the overall survival of patients with LUAD utilizing endoplasmic reticulum stress-related genes and screened out potential small molecular compounds, which could assist the clinician in making accurate decisions and better treat LUAD patients. Firstly, we downloaded 419 endoplasmic reticulum stress-related genes (ERSRGs) from Molecular Signatures Database (MSigDB). Secondly, we obtained information about the transcriptome profiling and corresponding clinical data of 59 normal samples and 535 lung adenocarcinoma samples from The Cancer Genome Atlas (TCGA) database. Next, we used the DESeq2 package to identify differentially expressed genes related to endoplasmic reticulum stress. We performed univariate Cox, least absolute shrinkage and selection operator (LASSO), and multivariate Cox regression analysis to establish a prognostic model for LUAD patients based on ERSRGs. Then, we carried out univariate and multivariate independent prognostic analysis of endoplasmic reticulum stress-related gene (ERSRG) score and some clinical traits of lung adenocarcinoma. Additionally, we developed a clinically applicable nomogram for predicting survival for LUAD patients over one, three, and five years. Moreover, we carried out a drug sensitivity analysis to identify novel small molecule compounds for LUAD treatment. Finally, we examined the tumor microenvironment (TME) and immune cell infiltrating analysis to explore the interactions between immune and cancer cells. 142 differentially expressed ERSRGs were identified by using the DESeq2 package. A prognostic model was built based on 7 differentially expressed ERSRGs after performing univariate Cox regression, LASSO regression, and multivariate Cox regression analysis. According to the results of univariate and multivariate independent prognostic analysis, we found ERSRG score can be used as an independent prognostic maker. Using the Kaplan-Meier curves, we found low-risk patients had higher survival probability than high-risk patients in both training set and test set. A nomogram was drawn to predict 1-, 3-, and 5-year survival probability. The calibration curves explained good performance of the model for the prediction of survival.
Phenformin, OSU-03012, GSK-650394 and KIN001-135 were identified as the drugs most likely to provide important information to clinicians about the treatment of LUAD patients. A prognostic prediction model was established based on 7 differentially expressed ERSRGs (PDX1, IGFBP1, DDIT4, PPP1R3G, CFTR, DERL3 and NUPR1), which could effectively predict the prognosis of LUAD patients and give a reference for clinical doctors to help LUAD patients to make better treatment tactics. Based on the 4 small molecule compounds (
Phenformin, OSU-03012, GSK-650394 and KIN001-135) we discovered, targeting endoplasmic reticulum stress-related genes may also be a therapeutic approach for LUAD patients.