Li Xue, Li Mingfeng, Zhao Tianyu, Zhang Jingyu
Central People's Hospital of Zhanjiang Zhanjiang, Guangdong, China.
Am J Cancer Res. 2023 Sep 15;13(9):4288-4304. eCollection 2023.
Kidney renal clear cell carcinoma (KIRC) is the most prevalent subtype of renal tumor. The underlying mechanisms governing KIRC initiation and progression are less known. The present study aimed to reveal novel hub genes associated with the initiation and progression of KIRC, which may be utilized as novel molecular biomarkers and therapeutic targets for the treatment of KIRC. The GSE6344 dataset from the Gene Expression Omnibus (GEO) database was integrated to identify differentially expressed genes (DEGs) using the limma package. Then, hub genes were identified and UALCAN, GEPIA, OncoDB, DriverDBv3, GENT2, and HPA databases were employed for the expression, survival, and methylation analyses. cBioPortal tool was used to investigate the genetic alterations, while CancerSEA, TIMER, DAVID, ENCORI, DrugBank, and GSCAlite were utilized to explore a few more hub gene-associated parameters. Finally, targeted bisulfite sequencing (bisulfite-seq), and RT-qPCR techniques were used to validate the expression and methylation level of the hub genes using Human RCC cell line 786-O, A-498, and normal renal tubular epithelial cell line HK-2. In total, 7299 DEGs were found between KIRC and normal samples in the GSE6344 dataset. Using STRING and Cytohubba analysis, four hub genes including VEGFA (vascular endothelial growth factor), ALB (Albumin), ENO2 (enolase 2), and CAVI1 (Caveolin 1) were selected as the hub genes. Further, it was validated through extensive analysis of TCGA datasets that these VEGA, ENO2, and CAV1 hub genes were significantly up-regulated, while ALB was significantly down-regulated in KIRC samples compared to controls. The dysregulation of these genes was found to be associated with the overall survival (OS) of the KIRC patients. Moreover, this study also revealed some novel links between VEGA, ALB, ENO2, and CAV1 expression and genetic alterations, promoter methylation status, immune cell infiltration, miRNAs, gene enrichment terms, and various chemotherapeutic drugs. The present study revealed a panel of four hub genes, which contributed to improving our understanding of the underlying molecular mechanisms of KIRC development and can be utilized as promising novel biomarkers for KIRC diagnosis, prognosis, and treatment.
肾透明细胞癌（KIRC）是最常见的肾肿瘤亚型。关于KIRC发生和发展的潜在机制尚鲜为人知。本研究旨在揭示与KIRC发生和发展相关的新的关键基因，这些基因可用作KIRC治疗的新型分子生物标志物和治疗靶点。整合来自基因表达综合数据库（GEO）的GSE6344数据集，使用limma软件包鉴定差异表达基因（DEG）。然后，鉴定关键基因，并利用UALCAN、GEPIA、OncoDB、DriverDBv3、GENT2和HPA数据库进行表达、生存和甲基化分析。使用cBioPortal工具研究基因改变，同时利用CancerSEA、TIMER、DAVID、ENCORI、DrugBank和GSCAlite探索更多与关键基因相关的参数。最后，使用靶向亚硫酸氢盐测序（亚硫酸氢盐测序）和RT-qPCR技术，利用人肾癌细胞系786-O、A-498和正常肾小管上皮细胞系HK-2验证关键基因的表达和甲基化水平。在GSE6344数据集中，共发现KIRC与正常样本之间有7299个DEG。使用STRING和Cytohubba分析，选择包括血管内皮生长因子（VEGFA）、白蛋白（ALB）、烯醇化酶2（ENO2）和小窝蛋白1（CAVI1）在内的四个关键基因作为关键基因。此外，通过对TCGA数据集的广泛分析验证，与对照相比，这些VEGA、ENO2和CAV1关键基因在KIRC样本中显著上调，而ALB显著下调。发现这些基因的失调与KIRC患者的总生存期（OS）相关。此外，本研究还揭示了VEGA、ALB、ENO2和CAV1表达与基因改变、启动子甲基化状态、免疫细胞浸润、miRNA、基因富集术语和各种化疗药物之间的一些新联系。本研究揭示了一组四个关键基因，有助于增进我们对KIRC发生潜在分子机制的理解，并可用作KIRC诊断、预后和治疗的有前景的新型生物标志物。
