Pan-Cancer Analysis for the Effects of ANGPT1 and TEK on Human Tumor Progression
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摘要:
目的 探讨血管生成素1（angiopoietins-1，ANGPT1）及其受体TEK（tyrosine kinase）在泛癌中的表达、预后及免疫浸润的情况。 方法 应用TIMER2.0、Kaplan-Meier plotter、UALCAN等数据库分析ANGPT1及TEK在泛癌中的表达、预后；利用SangerBox3.0及R软件分析ANGPT1、TEK与肿瘤突变负荷（tumor mutation burden，TMB）、微卫星不稳定（microsatellite instability，MSI）、免疫检查点（immune checkpoint，ICP）、免疫浸润的相关性；使用String数据库、GO与KEGG分析鉴定与ANGPT1和TEK相关的蛋白及调节通路。 结果 ANGPT1和TEK在多数肿瘤中低表达（P < 0.05）。ANGPT1、TEK低表达患者预后不良 （P < 0.05）。ANGPT1和TEK的表达水平与肾透明细胞癌、膀胱尿路上皮癌、乳腺浸润性癌等临床分期相关 （P < 0.05）。ANGPT1、TEK表达与肿瘤的TMB、MSI、ICP相关（P < 0.05），与免疫浸润正相关（P < 0.05）。与ANGPT1和TEK关系密切的基因有GRB2、PIK3R1、EGFR等，主要参与Grb2-EGFR、ERBB3：ERBB2、Shc-EGFR等复合物相关的生物学过程和功能，主要涉及ErbB信号通路。 结论 ANGPT1和TEK可能通过ErbB信号通路在肿瘤发生发展中起重要作用，有望成为多种癌症的潜在临床预后标志物。 Abstract:Objective To probe the expression level, prognostic value, and immune invasion of angipoietin-1 （ANGPT1）and its receptor tyrosine kinase （TEK）in pan-cancer. Methods TIMER2.0、Kaplan-Meier plotter and UALCAN etc. databases were used to analyze the expression, prognostic value of ANGPT1 and TEK in various types of tumors. SangerBox 3.0 and R software were used to analyze the relationship between ANGPT1 and TEK tumor mutational burden （TMB）, microsatellite instability （MSI）, immune checkpoint （ICP） and immune cell infiltration. String database, GO and KEGG analysis were used to identify proteins and regulatory pathways related to ANGPT1 and TEK. Results ANGPT1 and TEK showed low expression in most tumors （P < 0.05）. Patients with low expression of ANGPT1 and TEK had a worse prognosis （P < 0.05）. The expression levels of ANGPT1 and TEK were correlated with the clinical stages of clear cell renal carcinoma, bladder urothelial carcinoma, and invasive breast carcinoma （P < 0.05）. The expression of ANGPT1 and TEK was significantly correlated with TMB, MSI and ICP in various tumors （P < 0.05）, and was significantly positively correlated with immune invasion （P < 0.05）. The genes were closely related to ANGPT1 and TEK include GRB2, PIK3R1, EGFR, etc., which were mainly involved in a series of biological processes and functions related to Grb2-EGFR, ERBB3:ERBB2, Shc-EGFR and other complexes, mainly involved ErbB signaling pathway. Conclusion ANGPT1 and TEK may play an important role in tumorigenesis and development through the ErbB signaling pathway, and are expected to be potential clinical prognostic markers for various types of cancer. -
Key words:
- ANGPT1 /
- TEK /
- Pan-cancer analysis /
- The R Programming Language
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图 1 通过不同数据库分析ANGPT1与TEK在正常组织和不同肿瘤组织间的转录情况及蛋白表达量
A：通过TIMER数据库分析ANGPT1在不同肿瘤组织中相对于正常组织中的表达水平。B：通过TIMER数据库分析TEK在不同肿瘤组织中相对于正常组织中的表达水平。 C：通过UALCAN数据库分析ANGPT1在不同肿瘤组织的蛋白质组表达水平； D：通过UALCAN数据库分析TEK在不同肿瘤组织的蛋白质组表达水平。*P < 0.05；**P < 0.01；***P < 0.001。
Figure 1. The transcription and protein expression levels of ANGPT1 and TEK in normal tissues and different tumor tissues were analyzed by different databases
图 2 通过Kaplan-Meier plotter数据库分析ANGPT1、TEK表达在不同癌症中的预后价值
A：基于OS（总生存期）结果分析ANGPT1表达在不同肿瘤中的预后影响（P < 0.05）；B：基于OS（总生存期）结果分析TEK表达在不同肿瘤中的预后影响，*P < 0.05。
Figure 2. Analysis of the prognostic value of ANGPT1 and TEK expression in different cancers by Kaplan-Meier plotter database
图 3 ANGPT1和TEK在不同癌症类型中的基因免疫分析
A：ANGPT1表达水平与不同癌症类型的TMB（Tumor mutation burden）的相关性； B：ANGPT1表达水平与不同癌症类型的MSI（Microsatellite instability）评分的相关性； C：ANGPT1表达水平与不同癌症类型的免疫检查点的相关性； D：TEK表达水平与不同癌症类型的TMB（Tumor mutation burden）的相关性； E：TEK表达水平与不同癌症类型的MSI（Microsatellite instability）评分的相关性； F：TEK表达水平与不同癌症类型的免疫检查点的相关性。
Figure 3. Gene immunoassays of ANGPT1 and TEK in different cancer types
图 4 在不同癌症类型中ANGPT1和TEK的表达水平与免疫浸润细胞亚型的相关性分析（其中x轴为不同免疫细胞亚型，y轴为不同癌症类型，红色表示癌症和免疫细胞亚型之间的正相关。蓝色表示负相关。颜色越深，相关性越大。相关系数和P值显示在每个单元格中）
A：在不同癌症类型中ANGPT1表达水平与免疫浸润细胞亚型的相关性； B：在不同癌症类型中TEK表达水平与免疫浸润细胞亚型的相关性，*P < 0.05。
Figure 4. Correlation analysis of ANGPT1 and TEK expression levels with immune-infiltrating cell subtypes in different cancer types （The x-axis is for different immune cell subtypes，the y-axis is for different cancer types，and red indicates a positive correlation between cancer and immune cell subtype. Blue indicates a negative correlation. The darker the color，the greater the relevance. The correlation coefficient and P-value are displayed in each cell）
图 5 ANGPT1和TEK相关基因的蛋白相互作用网络与富集通路分析
A：通过TIMER数据库分析在不同癌症类型中ANGPT1对TEK表达量的影响； B：59个相关基因的蛋白质相互作用网络。通过STRING数据库检索得到的59个与ANGPT1和TEK相关的基因，利用Cytoscape软件将网络可视化，颜色节点代表已识别的蛋白质，从内到外，节点面积大小和颜色深浅程度代表节点的重要性强弱； C：ANGPT1和TEK相关基因GO分析的生物过程（BP）富集分析条目； D：ANGPT1和TEK相关基因GO分析的细胞组分（CC）富集分析条目； E：ANGPT1和TEK相关基因GO分析的分子功能（MF）富集分析条目； F：ANGPT1和TEK相关基因KEGG通路富集分析条目，*P < 0.05。
Figure 5. Analysis of protein interaction network and enrichment pathway of ANGPT1 and TEK-related genes
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[1] Bray F,Laversanne M,Weiderpass E,et al. The ever-increasing importance of cancer as a leading cause of premature death worldwide[J]. Cancer-Am Cancer Soc,2021,127(16):3029-3030. [2] 林国享,朱小东. 肿瘤血管生成的促进因素及其在肿瘤发生发展中的作用研究进展[J]. 广西医学,2020,42(3):334-337. [3] Chen W Z,Jiang J X,Yu X Y,et al. Endothelial cells in colorectal cancer[J]. World J Gastrointest Oncol,2019,11(11):946-956. doi: 10.4251/wjgo.v11.i11.946 [4] Lugano R,Ramachandran M,Dimberg A. Tumor angiogenesis: Causes,consequences,challenges and opportunities[J]. Cell Mol Life Sci,2020,77(9):1745-1770. doi: 10.1007/s00018-019-03351-7 [5] Omiyale A O. Primary vascular tumours of the kidney[J]. World J Clin Oncol,2021,12(12):1157-1168. doi: 10.5306/wjco.v12.i12.1157 [6] 何丹华,陈知英,陈国菊. 婴幼儿血管瘤异常表达基因分析[J]. 现代医药卫生,2023,39(2):199-203. [7] Li Y Y,Liu P,Zhou Y L,et al. Activation of angiopoietin-Tie2 signaling protects the kidney from ischemic injury by modulation of endothelial-specific pathways[J]. J Am Soc Nephrol,2023,34(6):969-987. doi: 10.1681/ASN.0000000000000098 [8] 徐文婵,刘珍银,陈钦谕,等. Tie2突变与儿童静脉畸形相关性研究[J]. 中华介入放射学电子杂志,2021,9(4):415-418. [9] Cam M,Charan M,Welker A M,et al. ΔNp73/ETS2 complex drives glioblastoma pathogenesis- targeting downstream mediators by rebastinib prolongs survival in preclinical models of glioblastoma[J]. Neuro Oncol,2020,22(3):345-356. doi: 10.1093/neuonc/noz190 [10] Liu W X,Gu S Z,Zhang S,et al. Angiopoietin and vascular endothelial growth factor expression in colorectal disease models[J]. World J Gastroentero,2015,21(9):2645-2650. doi: 10.3748/wjg.v21.i9.2645 [11] Zhou M,Wang B,Li H,et al. RNA-binding protein SAMD4A inhibits breast tumor angiogenesis by modulating the balance of angiogenesis program[J]. Cancer Sci,2021,112(9):3835-3845. doi: 10.1111/cas.15053 [12] Wu F T,Lee C R,Bogdanovic E,et al. Vasculotide reduces endothelial permeability and tumor cell extravasation in the absence of binding to or agonistic activation of Tie2[J]. Embo Mol Med,2015,7(6):770-787. doi: 10.15252/emmm.201404193 [13] Qin S,Yi M,Jiao D C,et al. Distinct Roles of VEGFA and ANGPT2 in lung adenocarcinoma and squamous cell carcinoma[J]. J Cancer,2020,11(1):153-167. doi: 10.7150/jca.34693 [14] 程阳,王一喆,金悦,等. ANGPT1基因在肺腺癌组织中的表达及其预后价值分析[J]. 现代肿瘤医学,2020,28(4):587-591. [15] Xue R,Sheng Y,Duan X,et al. Tie2-expressing monocytes as a novel angiogenesis-related cellular biomarker for non-small cell lung cancer[J]. Int J Cancer,2021,148(6):1519-1528. doi: 10.1002/ijc.33381 [16] Cai Z,Gong Z,Li Z,et al. Vascular extracellular matrix remodeling and hypertension[J]. Antioxid Redox Signal,2021,34(10):765-783. doi: 10.1089/ars.2020.8110 [17] Li Y,Chen D,Sun L,et al. Induced expression of VEGFC,ANGPT,and EFNB2 and their receptors characterizes neovascularization in proliferative diabetic retinopathy[J]. Invest Ophthalmol Vis Sci,2019,60(13):4084-4096. doi: 10.1167/iovs.19-26767 [18] Li Y,Liu P,Zhou Y,et al. Activation of angiopoietin-Tie2 signaling protects the kidney from ischemic injury by modulation of endothelial-specific pathways[J]. J Am Soc Nephrol,2023,34(6):969-987. doi: 10.1681/ASN.0000000000000098 [19] Staton C A,Hoh L,Baldwin A,et al. Angiopoietins 1 and 2 and Tie-2 receptor expression in human ductal breast disease[J]. Histopathology,2011,59(2):256-263. doi: 10.1111/j.1365-2559.2011.03920.x [20] G ü veli M E,Duranyildiz D,Karadeniz A,et al. Circulating serum levels of angiopoietin-1 and angiopoietin-2 in nasopharynx and larynx carcinoma patients[J]. Tumor Biol,2016,37(7):8979-8983. doi: 10.1007/s13277-015-4777-0 [21] Wen J,Li H Z,Ji Z G,et al. Expressions of receptor tyrosine kinases mRNA and protein in carcinoma of bladder[J]. Zhongguo Yi Xue Ke Xue Yuan Xue Bao,2011,33(4):393-396. [22] Yang F,Hu Y,Shao L,et al. SIRT7 interacts with TEK (TIE2) to promote adriamycin induced metastasis in breast cancer[J]. Cell Oncol,2021,44(6):1405-1424. doi: 10.1007/s13402-021-00649-2 [23] Ha M,Son Y R,Kim J,et al. TEK is a novel prognostic marker for clear cell renal cell carcinoma[J]. Eur Rev Med Pharmaco,2019,23(4):1451-1458. [24] Zhou S J,Xu B,Qi L,et al. Next-generation sequencing reveals mutational accordance between cell-free DNA from plasma,malignant pleural effusion and ascites and directs targeted therapy in a gastric cancer patient[J]. Cancer Biol Ther,2019,20(1):15-20. doi: 10.1080/15384047.2018.1504720 [25] Nong B,Su T,Jin M,et al. Immune-related gene ANGPT1 is an adverse biomarker for endometrial carcinoma[J]. Transl Cancer Res,2021,10(6):2962-2976. doi: 10.21037/tcr-21-671 [26] Katoh Y,Katoh M. Comparative integromics on Angiopoietin family members[J]. Int J Mol Med,2006,17(6):1145-1149. [27] Yao S,Dong S S,Ding J M,et al. Sex-specific SNP-SNP interaction analyses within topologically associated domains reveals ANGPT1 as a novel tumor suppressor gene for lung cancer[J]. Gene Chromosome Canc,2020,59(1):13-22. doi: 10.1002/gcc.22793 [28] Di Tacchio M,Macas J,Weissenberger J,et al. Tumor Vessel Normalization,Immunostimulatory Reprogramming,and Improved Survival in Glioblastoma with Combined Inhibition of PD-1,Angiopoietin-2,and VEGF[J]. Cancer Immunol Res,2019,7(12):1910-1927. doi: 10.1158/2326-6066.CIR-18-0865 [29] Zhang L,Li Z Y,Skrzypczynska K M,et al. Single-cell analyses inform mechanisms of myeloid-targeted therapies in colon cancer[J]. Cell,2020,181(2):442-459. doi: 10.1016/j.cell.2020.03.048 [30] Li G L,Tang J F,Tan W L,et al. The anti-hepatocellular carcinoma effects of polysaccharides from Ganoderma lucidum by regulating macrophage polarization via the MAPK/NF-κB signaling pathway[J]. Food Funct,2023,14(7):3155-3168. doi: 10.1039/D2FO02191A -
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