系统分析肾细胞癌中的 : 表达、预后、基因调控网络和调控靶点。
System analysis of in renal cell carcinoma: The expression, prognosis, gene regulation network and regulation targets.
机构信息
Guangdong Province Key Laboratory of Pharmacodynamic Constituents of TCM and New Drugs Research, 47885Jinan University, Guangzhou, China.
International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Development of Chinese Ministry of Education, College of Pharmacy, 47885Jinan University, Guangzhou, China.
出版信息
Int J Biol Markers. 2022 Mar;37(1):90-101. doi: 10.1177/17246008211063501. Epub 2021 Dec 6.
BACKGROUND
VEGFA is one of the most important regulators of angiogenesis and plays a crucial role in cancer angiogenesis and progression. Recent studies have highlighted a relationship between expression and renal cell carcinoma occurrence. However, the expression level, gene regulation network, prognostic value, and target prediction of in renal cell carcinoma remain unclear. Therefore, system analysis of the expression, gene regulation network, prognostic value, and target prediction of in patients with renal cell carcinoma is of great theoretical significance as there is a clinical demand for the discovery of new renal cell carcinoma treatment targets and strategies to further improve renal cell carcinoma treatment efficacy.
METHODS
This study used multiple free online databases, including cBioPortal, TRRUST, GeneMANIA, GEPIA, Metascape, UALCAN, LinkedOmics, Metascape, and TIMER for the abovementioned analysis.
RESULTS
was upregulated in patients with kidney renal clear cell carcinoma (KIRC) and kidney chromophobe (KICH), and downregulated in patients with kidney renal papillary cell carcinoma (KIRP). Moreover, genetic alterations of were found in patients with renal cell carcinoma as follows: 4% (KIRC), 8% (KICH), and 4% (KIRP). The promoter methylation of was lower and higher in patients with clinical stages of KIRC and stage 1 KIRP, respectively. expression significantly correlated with KIRC and KIRP pathological stages. Furthermore, patients with KICH and KIRP having low expression levels had a longer survival than those having high expression levels. and its neighboring genes functioned in the regulation of protein methylation and glycosylation, as well as muscle fiber growth and differentiation in patients with renal cell carcinoma. Gene Ontology enrichment analysis revealed that the functions of and its neighboring genes in patients with renal cell carcinoma are mainly related to cell adhesion molecule binding, catalytic activity, acting on RNA, ATPase activity, actin filament binding, protease binding, transcription coactivator activity, cysteine-type peptidase activity, and calmodulin binding. Transcription factor targets of and its neighboring genes in patients with renal cell carcinoma were found: HIF1A, TFAP2A, and ESR1 in KIRC; STAT3, NFKB1, and HIPK2 in KICH; and FOXO3, TFAP2A, and ETS1 in KIRP. We further explored the -associated kinase (ATM in KICH as well as CDK1 and AURKB in KIRP) and -associated microRNA (miRNA) targets (MIR-21 in KICH as well as MIR-213, MIR-383, and MIR-492 in KIRP). Furthermore, the following genes had the strongest correlation with expression in patients with renal cell carcinoma: , , and in KIRC; , , and in KICH; and , , and in KIRP. expression in patients with renal cell carcinoma was positively associated with immune cell infiltration, including CD8+T cells, CD4+T cells, macrophages, neutrophils, and dendritic cells.
CONCLUSIONS
This study revealed expression and potential gene regulatory network in patients with renal cell carcinoma, thereby laying a foundation for further research on the role of in renal cell carcinoma occurrence. Moreover, the study provides new renal cell carcinoma therapeutic targets and prognostic biomarkers as a reference for fundamental and clinical research.
背景
VEGFA 是血管生成最重要的调节因子之一，在癌症血管生成和进展中起着至关重要的作用。最近的研究强调了 表达与肾细胞癌发生之间的关系。然而， 在肾细胞癌中的表达水平、基因调控网络、预后价值和靶标预测仍然不清楚。因此，对肾细胞癌患者的 表达、基因调控网络、预后价值和靶标预测进行系统分析具有重要的理论意义，因为临床需要发现新的肾细胞癌治疗靶点和策略，以进一步提高肾细胞癌的治疗效果。
方法
本研究使用了多个免费的在线数据库，包括 cBioPortal、TRRUST、GeneMANIA、GEPIA、Metascape、UALCAN、LinkedOmics、Metascape 和 TIMER 进行上述分析。
结果
在肾透明细胞癌（KIRC）和肾嫌色细胞癌（KICH）患者中上调，在肾乳头状细胞癌（KIRP）患者中下调。此外，在肾细胞癌患者中发现了 的遗传改变：4%（KIRC）、8%（KICH）和 4%（KIRP）。 的启动子甲基化在 KIRC 和 KIRP 临床分期 1 期分别较低和较高。 表达与 KIRC 和 KIRP 病理分期显著相关。此外，KICH 和 KIRP 中 表达水平较低的患者的生存时间长于表达水平较高的患者。 和其邻近基因在肾细胞癌患者中参与了蛋白质甲基化和糖基化的调节，以及肌肉纤维的生长和分化。基因本体富集分析表明， 和其邻近基因在肾细胞癌患者中的功能主要与细胞粘附分子结合、催化活性、作用于 RNA、ATP 酶活性、肌动蛋白丝结合、蛋白酶结合、转录共激活因子活性、半胱氨酸型肽酶活性和钙调蛋白结合有关。在肾细胞癌患者中发现了 及其邻近基因的转录因子靶标：KIRC 中的 HIF1A、TFAP2A 和 ESR1；KICH 中的 STAT3、NFKB1 和 HIPK2；以及 KIRP 中的 FOXO3、TFAP2A 和 ETS1。我们进一步探讨了 和其邻近基因在肾细胞癌中的激酶（KICH 中的 ATM 以及 KIRP 中的 CDK1 和 AURKB）和 miRNA 靶标（KICH 中的 MIR-21 以及 KIRP 中的 MIR-213、MIR-383 和 MIR-492）。此外，在肾细胞癌患者中与 表达相关性最强的基因是：KIRC 中的 、 和 ；KICH 中的 、 和 ；以及 KIRP 中的 、 和 。肾细胞癌患者的 表达与免疫细胞浸润呈正相关，包括 CD8+T 细胞、CD4+T 细胞、巨噬细胞、中性粒细胞和树突状细胞。
结论
本研究揭示了 在肾细胞癌中的表达和潜在的基因调控网络，为进一步研究 在肾细胞癌发生中的作用奠定了基础。此外，该研究为基础和临床研究提供了新的肾细胞癌治疗靶点和预后生物标志物。
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