Hao Jiatao, Cao Yumeng, Yu Hui, Zong Lu, An Ruifang, Xue Yan
Department of Obstetrics and Gynecology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China.
Graduate School of China Medical University, China Medical University, Shenyang, China.
Front Genet. 2021 Sep 10;12:674613. doi: 10.3389/fgene.2021.674613. eCollection 2021.
MAPK kinase kinase 8 (MAP3K8) is involved in the regulation of MAPK cascades and immune responses. Differential expression of MAP3K8 is closely correlated with tumorigenesis. In this study, we used bioinformatics tools to explore expression level, prognostic values, and interactive networks of MAP3K8 in renal clear cell carcinoma (ccRCC). Differential expression of MAP3K8 was determined by TIMER2.0, UALCAN, and Oncomine Platform. For exploration of MAP3K8 mutation profile, TIMER2.0, DriverDBv3, and cBioPortal were used. The survival module of GEPIA, UALCAN, and DriverDBv3 was used to examine the prognostic value of MAP3K8. Immune infiltration was estimated by TIMER, TIDE, CIBERSORT, CIBERSORT-ABS, QUANTISEQ, XCELL, MCPCOUNTER, and EPIC algorithms. PPI networks and functional enrichment analysis were constructed using GeneMANIA, Cytoscape, and Metascape. The co-expression module in cBioPortal was used to find genes that are correlated with MAP3K8 in mRNA expression. Compared to normal renal samples, ccRCC (3.08-fold change, = 1.50E-7; 1.10-fold change, = 3.00E-3), papillary RCC (2.24-fold change, = 1.86E-4), and hereditary ccRCC (1.98-fold change, = 1.69E-9) have significantly higher levels of MAP3K8 expression. Compared to Grade 1 ccRCC samples, Grade 2 ( = 1.28E-3) and Grade 3 ( = 7.41E-4) cases have higher levels of MAP3K8 methylation. Percentage of patients harboring MAP3K8 mutation is 0.3% from TIMER2.0 and 0.2 to 11.5% from cBioPortal. High levels of MAP3K8 expression were associated with poorer overall survival (OS) in ccRCC (GEPIA: Log-rank = 0.60E-2, HR = 1.5; DriverDBv3: Log-rank = 1.68E-7, HR = 2.21; UALCAN: = 0.20E-2). MAP3K8 was positively correlated with the presence of T cell regulatory (Tregs) (QUANTISEQ: Rho = 0.33, = 1.59E-13). PPI network and functional enrichment analyses revealed that MAP3K8 correlated with NFKBIZ, MIAT, PARP15, CHFR, MKNK1, and ERMN, which was mainly involved in I-kappaB kinase/NF-kappaB and toll-like receptor signaling pathways. MAP3K8 overexpression was correlated with damaged survival in ccRC and may play a crucial role in cancer-related inflammation via I-kappaB kinase/NF-kappaB and toll-like receptor signaling pathways.
丝裂原活化蛋白激酶激酶激酶8（MAP3K8）参与丝裂原活化蛋白激酶级联反应和免疫反应的调控。MAP3K8的差异表达与肿瘤发生密切相关。在本研究中，我们使用生物信息学工具来探究MAP3K8在肾透明细胞癌（ccRCC）中的表达水平、预后价值及相互作用网络。通过TIMER2.0、UALCAN和Oncomine平台确定MAP3K8的差异表达。为探究MAP3K8突变谱，使用了TIMER2.0、DriverDBv3和cBioPortal。利用GEPIA、UALCAN和DriverDBv3的生存模块来检验MAP3K8的预后价值。通过TIMER、TIDE、CIBERSORT、CIBERSORT - ABS、QUANTISEQ、XCELL、MCPCOUNTER和EPIC算法估计免疫浸润情况。使用GeneMANIA、Cytoscape和Metascape构建蛋白质 - 蛋白质相互作用（PPI）网络和功能富集分析。利用cBioPortal中的共表达模块查找在mRNA表达上与MAP3K8相关的基因。与正常肾组织样本相比，ccRCC（变化倍数为3.08，P = 1.50E - 7；变化倍数为1.10，P = 3.00E - 3）、乳头状肾细胞癌（变化倍数为2.24，P = 1.86E - 4）和遗传性ccRCC（变化倍数为1.98，P = 1.69E - 9）中MAP3K8的表达水平显著更高。与1级ccRCC样本相比，2级（P = 1.28E - 3）和3级（P = 7.41E - 4）病例中MAP3K8的甲基化水平更高。来自TIMER2.0的携带MAP3K8突变的患者百分比为0.3%，来自cBioPortal的为0.2%至11.5%。ccRCC中高水平的MAP3K8表达与较差的总生存期（OS）相关（GEPIA：对数秩检验P = 0.60E - 2，风险比[HR] = 1.5；DriverDBv3：对数秩检验P = 1.68E - 7，HR = 2.21；UALCAN：P = 0.20E - 2）。MAP3K8与调节性T细胞（Tregs）的存在呈正相关（QUANTISEQ：相关系数Rho = 0.33，P = 1.59E - 13）。PPI网络和功能富集分析显示，MAP3K8与NFKBIZ、MIAT、PARP15、CHFR、MKNK1和ERM N相关，主要参与I - κB激酶/NF - κB和Toll样受体信号通路。MAP3K8的过表达与ccRCC中生存受损相关，可能通过I - κB激酶/NF - κB和Toll样受体信号通路在癌症相关炎症中起关键作用。
