Nayak Chirasmita, Singh Sanjeev Kumar
Computer-Aided Drug Design and Molecular Modeling Lab, Department of Bioinformatics, Alagappa University, Karaikudi 630003, Tamil Nadu, India.
ACS Omega. 2022 Jun 22;7(26):22531-22550. doi: 10.1021/acsomega.2c01820. eCollection 2022 Jul 5.
Glioblastoma (GBM) is the most devastating and frequent type of primary brain tumor with high morbidity and mortality. Despite the use of surgical resection followed by radio- and chemotherapy as standard therapy, the progression of GBM remains dismal with a median overall survival of <15 months. GBM embodies a populace of cancer stem cells (GSCs) that is associated with tumor initiation, invasion, therapeutic resistance, and post-treatment reoccurrence. However, understanding the potential mechanisms of stemness and their candidate biomarkers remains limited. Hence in this investigation, we aimed to illuminate potential candidate hub genes and key pathways associated with the pathogenesis of GSC in the development of GBM. The integrated analysis discovered differentially expressed genes (DEGs) between the brain cancer tissues (GBM and GSC) and normal brain tissues. Multiple approaches, including gene ontology (GO) analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis, were employed to functionally annotate the DEGs and visualize them through the R program. The significant hub genes were identified through the protein-protein interaction network, Venn diagram analysis, and survival analysis. We observed that the upregulated DEGs were prominently involved in the ECM-receptor interaction pathway. The downregulated genes were mainly associated with the axon guidance pathway. Five significant hub genes (CTNNB1, ITGB1, TNC, EGFR, and SHOX2) were screened out through multiple analyses. GO and KEGG analyses of hub genes uncovered that these genes were primarily enriched in disease-associated pathways such as the inhibition of apoptosis and the DNA damage repair mechanism, activation of the cell cycle, EMT (epithelial-mesenchymal transition), hormone AR (androgen receptor), hormone ER (estrogen receptor), PI3K/AKT (phosphatidylinositol 3-kinase and AKT), RTK (receptor tyrosine kinase), and TSC/mTOR (tuberous sclerosis complex and mammalian target of rapamycin). Consequently, the epigenetic regulatory network disclosed that hub genes played a vital role in the progression of GBM. Finally, candidate drugs were predicted that can be used as possible drugs to treat GBM patients. Overall, our investigation offered five hub genes (CTNNB1, ITGB1, TNC, EGFR, and SHOX2) that could be used as precise diagnostic and prognostic candidate biomarkers of GBM and might be used as personalized therapeutic targets to obstruct gliomagenesis.
胶质母细胞瘤（GBM）是最具破坏性且最常见的原发性脑肿瘤类型，发病率和死亡率都很高。尽管采用手术切除联合放化疗作为标准治疗方法，但GBM的进展仍然不容乐观，中位总生存期不到15个月。GBM中存在一群癌症干细胞（GSCs），它们与肿瘤的起始、侵袭、治疗抗性以及治疗后复发相关。然而，对干性的潜在机制及其候选生物标志物的了解仍然有限。因此，在本研究中，我们旨在阐明与GBM发生发展过程中GSC发病机制相关的潜在候选枢纽基因和关键通路。综合分析发现了脑癌组织（GBM和GSC）与正常脑组织之间的差异表达基因（DEGs）。我们采用了多种方法，包括基因本体（GO）分析和京都基因与基因组百科全书（KEGG）通路分析，对DEGs进行功能注释，并通过R程序将其可视化。通过蛋白质-蛋白质相互作用网络、维恩图分析和生存分析确定了重要的枢纽基因。我们观察到上调的DEGs主要参与细胞外基质-受体相互作用通路。下调的基因主要与轴突导向通路相关。通过多重分析筛选出了五个重要的枢纽基因（CTNNB1、ITGB1、TNC、EGFR和SHOX2）。对枢纽基因的GO和KEGG分析发现，这些基因主要富集于与疾病相关的通路，如细胞凋亡抑制和DNA损伤修复机制、细胞周期激活、上皮-间质转化（EMT）、激素AR（雄激素受体）、激素ER（雌激素受体）、PI3K/AKT（磷脂酰肌醇3-激酶和AKT）、受体酪氨酸激酶（RTK）以及结节性硬化症复合体和哺乳动物雷帕霉素靶蛋白（TSC/mTOR）。因此，表观遗传调控网络揭示了枢纽基因在GBM进展中起着至关重要的作用。最后，预测了可作为治疗GBM患者的可能药物的候选药物。总体而言，我们的研究提供了五个枢纽基因（CTNNB1、ITGB1、TNC、EGFR和SHOX2），它们可用作GBM精确的诊断和预后候选生物标志物，并可能作为个性化治疗靶点来阻碍胶质瘤的发生。
