Department of Dermatology and Allergy, University Hospital, Ludwig Maximilians University of Munich (LMU) Munich, Munich, Germany.
Dr. Phillip Frost Department of Dermatology & Cutaneous Surgery, Miller School of Medicine, University of Miami, Miami, United States.
Front Immunol. 2023 Mar 1;14:1118458. doi: 10.3389/fimmu.2023.1118458. eCollection 2023.
Human papilloma virus (HPV)-related cancers are global health challenge. Insufficient comprehension of these cancers has impeded the development of novel therapeutic interventions. Bioinformatics empowered us to investigate these cancers from new entry points.
DNA methylation data of cervical squamous cell carcinoma (CESC) and anal squamous cell carcinoma (ASCC) were analyzed to identify the significantly altered pathways. Through analyses integrated with RNA sequencing data of genes in these pathways, genes with strongest correlation to the TNM staging of CESC was identified and their correlations with overall survival in patients were assessed. To find a potential promising drug, correlation analysis of gene expression levels and compound sensitivity was performed. experiments were conducted to validate these findings. We further performed molecular docking experiments to explain our findings.
Significantly altered pathways included immune, HPV infection, oxidative stress, ferroptosis and necroptosis. 10 hub genes in these pathways (PSMD11, RB1, SAE1, TAF15, TFDP1, CORO1C, JOSD1, CDC42, KPNA2 and NUP62) were identified, in which only CDC42 high expression was statistically significantly correlated with overall survival (Hazard Ratio: 1.6, = 0.045). Afatinib was then screened out to be tested. experiments exhibited that the expression level of CDC42 was upregulated in HaCaT/A431 cells transfected with HPV E6 and E7, and the inhibitory effect of afatinib on proliferation was enhanced after transfection. CDC42-GTPase-effector interface-EGFR-afatinib was found to be a stable complex with a highest ZDOCK score of 1264.017.
We identified CDC42 as a pivotal gene in the pathophysiology of HPV-related cancers. The upregulation of CDC42 could be a signal for afatinib treatment and the mechanism in which may be an increased affinity of EGFR to afatinib, inferred from a high stability in the quaternary complex of CDC42-GTPase-effector interface-EGFR-afatinib.
人乳头瘤病毒（HPV）相关癌症是全球健康挑战。对这些癌症的理解不足阻碍了新型治疗干预措施的发展。生物信息学使我们能够从新的切入点研究这些癌症。
分析宫颈鳞状细胞癌（CESC）和肛门鳞状细胞癌（ASCC）的 DNA 甲基化数据，以确定显著改变的途径。通过对这些途径中基因的 RNA 测序数据进行分析，确定与 CESC 的 TNM 分期相关性最强的基因，并评估其与患者总生存期的相关性。为了找到一种有潜力的有希望的药物，对基因表达水平与化合物敏感性的相关性进行了分析。进行了实验来验证这些发现。我们还进一步进行了分子对接实验来解释我们的发现。
显著改变的途径包括免疫、HPV 感染、氧化应激、铁死亡和坏死性凋亡。在这些途径中，鉴定出 10 个关键基因（PSMD11、RB1、SAE1、TAF15、TFDP1、CORO1C、JOSD1、CDC42、KPNA2 和 NUP62），其中只有 CDC42 高表达与总生存期呈统计学显著相关（危险比：1.6，=0.045）。然后筛选出阿法替尼进行测试。实验表明，在转染 HPV E6 和 E7 的 HaCaT/A431 细胞中，CDC42 的表达水平上调，转染后阿法替尼对增殖的抑制作用增强。CDC42-GTPase 效应器界面-EGFR-阿法替尼被发现是一个稳定的复合物，具有最高的 ZDOCK 评分 1264.017。
我们确定 CDC42 是 HPV 相关癌症病理生理学中的关键基因。CDC42 的上调可能是阿法替尼治疗的信号，其机制可能是 EGFR 与阿法替尼的亲和力增加，这可以从 CDC42-GTPase 效应器界面-EGFR-阿法替尼的四级复合物的高稳定性推断出来。
