Javed Muhammad, Bukhari Rimsha Sadia, Rasool Rubab, Alhomrani Majid, Alghamdi Saleh A, Habeeballah Hamza, Ramzan Faiqah, Baothman Bandar K, Kashif Muhammad, Almaghrabi Sarah, Izmirly Abdullah M, Khalid Syed Yousaf
Primary and Secondary Health Care Department Lahore, Pakistan.
Fatima Jinnah Medical University Lahore, Pakistan.
Am J Cancer Res. 2023 May 15;13(5):1826-1844. eCollection 2023.
Head and neck squamous cell carcinoma (HNSC) is the 6 most common cancer around the globe; its underlying molecular mechanisms and accurate molecular markers are still lacking. In this study, we explored hub genes and their potential signaling pathways through which these genes participate in the development of HNSC. The GSE23036 gene microarray dataset was attained from the GEO (Gene Expression Omnibus) database. Hub genes were identified via the Cytohubba plug-in application of the Cytoscape. The Cancer Genome Atlas (TCGA) datasets and cell lines (HOK and FuDu) were used to evaluate expression variations in the hub genes. Moreover, promoter methylation, genetic alteration, gene enrichment, miRNA network, and immunocyte infiltration analysis were also performed to confirm the oncogenic role and biomarker potential of the hub genes in HNSC patients. Based on the hub gene analysis results, four hub genes, including KNTC1 (Kinetochore Associated 1), CEP55 (Centrosomal protein of 55 kDa), AURKA (Aurora A Kinase), and ECT2 (Epithelial Cell Transforming 2), with the highest degree scores were denoted as hub genes. All these four genes were significantly up-regulated in HNSC clinical samples and cell lines relative to their counterparts. Overexpression of KNTC1, CEP55, AURKA, and ECT2 was also associated with poor survival and various clinical parameters of the HNSC patients. Methylation analysis through targeted bisulfite sequencing of HOK and FuDu cell lines revealed that the overexpression of KNTC1, CEP55, AURKA, and ECT2 hub genes was due to their promoter hypomethylation. Moreover, higher expressions of KNTC1, CEP55, AURKA, and ECT2 were positively correlated with the abundance of the CD4+ T cells and macrophage while with the reduction of CD8+ T cells in HNSC samples. Finally, gene enrichment analysis showed that all hub genes are involved in "nucleoplasm, centrosome, mitotic spindle, and cytosol" pathways. In conclusion, the KNTC1, CEP55, AURKA, and ECT2 genes could be potential biomarkers for HNSC patients and provide a novel insight into the diagnosis and treatment of the disease.
头颈部鳞状细胞癌（HNSC）是全球第六大常见癌症；其潜在的分子机制和准确的分子标志物仍然缺乏。在本研究中，我们探索了枢纽基因及其潜在的信号通路，这些基因通过这些通路参与HNSC的发展。GSE23036基因微阵列数据集来自GEO（基因表达综合数据库）数据库。通过Cytoscape的Cytohubba插件应用程序鉴定枢纽基因。癌症基因组图谱（TCGA）数据集和细胞系（HOK和FuDu）用于评估枢纽基因的表达变化。此外，还进行了启动子甲基化、基因改变、基因富集分析、miRNA网络分析和免疫细胞浸润分析，以确认枢纽基因在HNSC患者中的致癌作用和生物标志物潜力。基于枢纽基因分析结果，将度值最高的四个枢纽基因，包括KNTC1（动粒相关蛋白1）、CEP55（55 kDa中心体蛋白）、AURKA（极光激酶A）和ECT2（上皮细胞转化蛋白2），确定为枢纽基因。相对于对照，这四个基因在HNSC临床样本和细胞系中均显著上调。KNTC1、CEP55、AURKA和ECT2的过表达也与HNSC患者的不良生存和各种临床参数相关。通过对HOK和FuDu细胞系进行靶向亚硫酸氢盐测序的甲基化分析表明，KNTC1、CEP55、AURKA和ECT2枢纽基因的过表达是由于其启动子低甲基化。此外，在HNSC样本中，KNTC1、CEP55、AURKA和ECT2的高表达与CD4 + T细胞和巨噬细胞的丰度呈正相关，而与CD8 + T细胞的减少呈正相关。最后，基因富集分析表明，所有枢纽基因都参与“核质、中心体、有丝分裂纺锤体和细胞质”通路。总之，KNTC1、CEP55、AURKA和ECT2基因可能是HNSC患者的潜在生物标志物，并为该疾病的诊断和治疗提供了新的见解。
