基于生物信息学和免疫组化染色，将AGAP2鉴定为透明细胞肾细胞癌的预后生物标志物。

Identify AGAP2 as prognostic biomarker in clear cell renal cell carcinoma based on bioinformatics and IHC staining.

作者信息

Xu Zekun, Wang Yuxuan, Xu Jiangnan, Ang Xiaojie, Ge Nianxin, Xu Min, Pei Changsong

机构信息

Department of Urology Surgery, Affiliated Jinhua Hospital, Zhejiang University School of Medicine, Jinhua, China.

Guangxi Medical University, Nanning, China.

出版信息

Heliyon. 2023 Feb 5;9(2):e13543. doi: 10.1016/j.heliyon.2023.e13543. eCollection 2023 Feb.

DOI:10.1016/j.heliyon.2023.e13543

PMID:36846683

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC9947311/

Abstract

BACKGROUND

Arf GTPase-activating proteins are aberrantly expressed in a variety of tumors, but their role in clear cell renal cell carcinoma (ccRCC) was unclear. Exploring the biological role of Arf GAP with GTP binding protein like domain, Ankyrin repeat and PH domain 2 (AGAP2) in ccRCC could improve our understanding on the aggressiveness and immune relevance of ccRCC.

METHODS

The expression of AGAP2 was analyzed based on the Cancer Genome Atlas (TCGA) database and verified in ccRCC samples using immunohistochemistry. The association between AGAP2 and clinical cancer stages was explored by TCGA dataset and UALCAN. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis were performed to analyze the biological functions of AGAP2-related genes. Moreover, the relationship between AGAP2 and immune cell infiltration was investigated with TIME and TCGA dataset.

RESULTS

Compared to normal tissues, AGAP2 was upregulated in ccRCC tissues. Higher expression of AGAP2 was associated with clinical cancer stages, TNM stages, pathologic stages, and status. Prognostic analysis on AGAP2 showed that AGAP2 overexpression was associated with KIRC overall survival (OS) reduction (P = 0.019). However, higher expression of AGAP2 may improve the OS of CESC (P = 0.002), THYM (P = 0.006) and UCEC (P = 0.049). GO and KEGG analysis showed that AGAP2-related genes was related to T cell activation, immune activity and PD-L1 expression and PD-1 checkpoint pathway. Furthermore, our study showed that AGAP2 were significantly associated with T cells, Cytotoxic cells, Treg, Th1 cells, CD8 T cells, T helper cells. And AGAP2 expression level affected the abundance of immune cells infiltration. The infiltrating level of immune cells was different between the AGAP2 high-expression and low-expression groups.

CONCLUSION

The expression of AGAP2 in ccRCC was higher than that in normal kidney tissues. It was significantly associated with clinical stage, poor prognosis, and immune cell infiltration. Therefore, AGAP2 may become an important component for ccRCC patients who receive precision cancer therapy and may be a promising prognostic biomarker.

摘要

背景

Arf GTP酶激活蛋白在多种肿瘤中异常表达，但其在透明细胞肾细胞癌（ccRCC）中的作用尚不清楚。探索具有GTP结合蛋白样结构域、锚蛋白重复序列和PH结构域2（AGAP2）的Arf GAP在ccRCC中的生物学作用，有助于我们更好地理解ccRCC的侵袭性和免疫相关性。

方法

基于癌症基因组图谱（TCGA）数据库分析AGAP2的表达，并使用免疫组织化学在ccRCC样本中进行验证。通过TCGA数据集和UALCAN探索AGAP2与临床癌症分期之间的关联。进行基因本体论（GO）和京都基因与基因组百科全书（KEGG）分析，以分析AGAP2相关基因的生物学功能。此外，利用TIME和TCGA数据集研究AGAP2与免疫细胞浸润之间的关系。

结果

与正常组织相比，AGAP2在ccRCC组织中上调。AGAP2的高表达与临床癌症分期、TNM分期、病理分期和状态相关。对AGAP2的预后分析表明，AGAP2过表达与肾透明细胞癌（KIRC）总生存期（OS）降低相关（P = 0.019）。然而，AGAP2的高表达可能改善子宫颈鳞状细胞癌（CESC）（P = 0.002）、胸腺癌（THYM）（P = 0.006）和子宫内膜癌（UCEC）（P = 0.049）的OS。GO和KEGG分析表明，AGAP2相关基因与T细胞活化、免疫活性以及程序性死亡受体配体1（PD-L1）表达和程序性死亡受体1（PD-1）检查点通路相关。此外，我们的研究表明，AGAP2与T细胞、细胞毒性细胞、调节性T细胞（Treg）、辅助性T细胞1（Th1）、CD8 + T细胞、辅助性T细胞显著相关。并且AGAP2表达水平影响免疫细胞浸润的丰度。AGAP2高表达组和低表达组之间免疫细胞的浸润水平不同。