背景:锌指E盒结合homeobox1(ZEB1)和ZEB2是两个与失巢凋亡相关的转录因子。这两个基因的mRNA表达在肾透明细胞癌(KIRC)中显著升高,这与不良的生存有关。同时,KIRC中ZEB1和ZEB2上调的机制和临床意义尚不清楚.
方法:通过癌症基因组图谱(TCGA)数据库和基因表达综合(GEO)数据库,表达式配置文件,评估ZEB1和ZEB2的预后价值和受试者工作特征曲线(ROCs)。在TCGA-KIRC数据库中进一步评估ZEB1和ZEB2与失巢凋亡的相关性。接下来,miRTarBase,miRDB,和TargetScan用于预测靶向ZEB1和ZEB2的microRNA,TCGA-KIRC数据库用于辨别microRNA的差异并建立microRNA和ZEB之间的关联。TCGA,TIMER,TISIB,和TISCH用于分析肿瘤免疫浸润。
结果:发现KIRC患者ZEB1和ZEB2的表达与组织学分级有关。Kaplan-Meier生存分析显示,具有低ZEB1或ZEB2水平的KIRC患者的生存率明显降低。同时,ZEB1和ZEB2与失巢凋亡密切相关,并受microRNA调控。我们使用单变量Cox和LASSO回归分析构建了一个风险模型,以鉴定两个microRNA(hsa-miR-130b-3p和hsa-miR-138-5p)。此外,ZEB1和ZEB2调节KIRC肿瘤微环境中的免疫细胞侵袭。
结论:Anoikis,细胞毒性免疫细胞浸润,患者生存结局与KIRC中ZEB1和ZEB2mRNA上调相关。ZEB1和ZEB2受微小RNA调控。
BACKGROUND: Zinc finger E-box binding homEeobox 1 (ZEB1) and ZEB2 are two anoikis-related transcription factors. The mRNA expressions of these two genes are significantly increased in kidney renal clear cell carcinoma (KIRC), which are associated with poor survival. Meanwhile, the mechanisms and clinical significance of ZEB1 and ZEB2 upregulation in KIRC remain unknown.
METHODS: Through the Cancer Genome Atlas (TCGA) database and Gene Expression Omnibus (GEO) database, expression profiles, prognostic value and receiver operating characteristic curves (ROCs) of ZEB1 and ZEB2 were evaluated. The correlations of ZEB1 and ZEB2 with anoikis were further assessed in TCGA-KIRC database. Next, miRTarBase, miRDB, and TargetScan were used to predict microRNAs targeting ZEB1 and ZEB2, and TCGA-KIRC database was utilized to discern differences in microRNAs and establish the association between microRNAs and ZEBs. TCGA, TIMER, TISIDB, and TISCH were used to analyze tumor immune infiltration.
RESULTS: It was found that ZEB1 and ZEB2 expression were related with histologic grade in KIRC patient. Kaplan-Meier survival analyses showed that KIRC patients with low ZEB1 or ZEB2 levels had a significantly lower survival rate. Meanwhile, ZEB1 and ZEB2 are closely related to anoikis and are regulated by microRNAs. We constructed a risk model using univariate Cox and LASSO regression analyses to identify two microRNAs (hsa-miR-130b-3p and hsa-miR-138-5p). Furthermore, ZEB1 and ZEB2 regulate immune cell invasion in KIRC tumor microenvironments.
CONCLUSIONS: Anoikis, cytotoxic immune cell infiltration, and patient survival outcomes were correlated with ZEB1 and ZEB2 mRNA upregulation in KIRC. ZEB1 and ZEB2 are regulated by microRNAs.