Xiao Guan-Fa, Yan Xin, Chen Zhao, Zhang Ren-Jie, Liu Tong-Zu, Hu Wan-Li
Department of Urology, Zhongnan Hospital of Wuhan University, Wuhan, China.
Department of Pediatric surgery, Ganzhou Maternal and Child Health Hospital, Ganzhou, China.
Front Genet. 2020 Aug 18;11:810. doi: 10.3389/fgene.2020.00810. eCollection 2020.
Clear cell renal cell carcinoma (ccRCC) is one of the most common histological subtypes of renal cancer, with a poor prognosis. Our study aimed to identify a biomarker that is significantly associated with ccRCC prognosis and novel immunotherapeutic targets, as well as some novel molecular drugs for ccRCC. Based on the overlap of The Cancer Genome Atlas (TCGA)-Kidney Renal Clear Cell Carcinoma (KIRC) data and the ImmPort database, we obtained 1,292 immune-related genes (IRGs) and constructed a weighed co-expression network based on the IRGs. A total of 39 hub genes were screened out in three modules. CTLA4, which had the highest connectivity degree among the screened genes in a protein-protein interaction network (degree = 24), was selected. Internal validation based on the GEPIA database revealed that patients with a higher expression of CTLA4 had a significantly shorter overall survival time and disease-free survival time. Expression of CTLA4 was also closely correlated with local recurrence, pathologic stage, and immune infiltration level. External validation based on the Oncomine database and merged microarray-acquired dataset validated the mRNA expression level of hub genes. Gene-set enrichment analysis revealed that six KEGG signaling pathways, which were significantly associated with CTLA4, were enriched on immune-related pathways. Further analysis according to the TIMER database demonstrated that CTLA4 expression was positively related to dendritic cells (cor = 0.446, = 1.32E-23) and negatively associated with tumor purity (cor = -0.267, = 5.51E-09). Finally, we screened out 293 differentially expressed genes by integrating six datasets from the GEO database. The Connectivity Map (CMap) analysis revealed the strong potential of three small molecule drugs (monensin, quercetin, and fenbufen) for ccRCC treatment. In conclusion, CTLA4 was identified and validated in prognosis of ccRCC. CTLA4 may be a new prognostic biomarker and immunotherapeutic target for ccRCC. Monensin, quercetin, and fenbufen may be novel choices for ccRCC treatment.
透明细胞肾细胞癌（ccRCC）是肾癌最常见的组织学亚型之一，预后较差。我们的研究旨在确定一种与ccRCC预后显著相关的生物标志物、新的免疫治疗靶点以及一些用于ccRCC的新型分子药物。基于癌症基因组图谱（TCGA）-肾透明细胞癌（KIRC）数据与免疫数据库（ImmPort）的重叠，我们获得了1292个免疫相关基因（IRGs），并基于这些IRGs构建了加权共表达网络。在三个模块中总共筛选出39个核心基因。选择了在蛋白质-蛋白质相互作用网络中筛选出的基因中连接度最高的CTLA4（连接度=24）。基于GEPIA数据库的内部验证显示，CTLA4表达较高的患者总生存时间和无病生存时间显著缩短。CTLA4的表达也与局部复发、病理分期和免疫浸润水平密切相关。基于Oncomine数据库和合并的微阵列获得的数据集的外部验证证实了核心基因的mRNA表达水平。基因集富集分析显示，与CTLA4显著相关的6条KEGG信号通路在免疫相关通路上富集。根据TIMER数据库的进一步分析表明，CTLA4表达与树突状细胞呈正相关（cor = 0.446，P = 1.32E-23），与肿瘤纯度呈负相关（cor = -0.267，P = 5.51E-09）。最后，通过整合来自GEO数据库的6个数据集，我们筛选出293个差异表达基因。连接图谱（CMap）分析揭示了三种小分子药物（莫能菌素、槲皮素和芬布芬）用于ccRCC治疗的强大潜力。总之，CTLA4在ccRCC预后中得到了鉴定和验证。CTLA4可能是ccRCC的一种新的预后生物标志物和免疫治疗靶点。莫能菌素、槲皮素和芬布芬可能是ccRCC治疗的新选择。
