Mahmoud Ashraf Attia, Raih Mohd Firdaus, Sage Edison Eukun, Ali Qurashi M, Suliman Omnia H, Ibrahim Sabah A E, Mohamed Osama, Abdelrazeg Samar, Mohamed Sofia B
Department of Bioinformatics and Biostatistics, National University Biomedical Research Institute, National University-Sudan, Khartoum, Sudan.
Department of Applied Physics, Faculty of Science and Technology, Universiti Kebangsaan Malaysia, UKM Bangi, Selangor, Malaysia.
PLoS One. 2025 May 7;20(5):e0307859. doi: 10.1371/journal.pone.0307859. eCollection 2025.
The tumor suppressor protein p53 (TP53) is frequently mutated in various types of human malignancies, including HNSCC, which affects tumor growth, prognosis, and treatment. Gaining insight into the impact of TP53 mutations in HNSCC is crucial for developing new diagnostic and therapeutic methods. In this study, we aimed to investigate the influence of mutations on the structure and functions of the TP53 protein and miRNA expression using computational analysis. The genomic data of patients with HNSCC were obtained from TCGA, and the impact of mutations on the TP53 gene was investigated using different bioinformatics tools. Results: The findings showed that the TP53 mutations increased TP53 expression levels in HNSCC and were associated with a poor prognosis. Furthermore, hsa-mir-133b expression was reduced in TP53-mutated samples, significantly affecting patient survival in HNSCC. Six mutations, including R273C, G105C, G266E, Q136H/P, and R280G, were identified as deleterious, carcinogenic, driver, highly conserved, and exposed. These mutations were located in the P53 domain, and PTM analysis revealed that R280G and R273C are at a methylation site, and R273C, Q136H/P, and R280G are located in the protein pocket. The docking research indicated that these mutations decreased the binding affinity for DNA, with R273C, R280G, G266E, and G105C displaying the most significant differences. The molecular dynamics analysis indicates that R280G, Q136H, and G105C mutations confer a gain of function by stabilizing the TP53-substrate complex. Conclusions: Based on the research findings, the mutations on TP53 were found to have an impact on protein and miRNA expression, development, survival, and progression of HNSCC patients, and has-mir-133b could be a promising novel biomarker for monitoring the progression of HNSCC. It was discovered that G105C and Q136H/P, as novel mutations, affect the function and structure of proteins causing HNSCC, which indicates that they could be interesting subjects for further investigation, diagnostics, and therapeutic strategies. Furthermore, the precise positioning of R280G and R273C within the methylation site and Q136H/P in the binding site has been documented for the first time. Moreover, the G105C, Q136H, and R280G mutations that stabilized TP53 structure and altered its interaction dynamics with substrates may serve as novel potential diagnostic biomarkers in cancer, guiding patient stratification and personalized treatment strategies. The molecular dynamics analysis provides insights into how specific TP53 mutations impact protein structure, stability, and function upon substrate binding, highlighting their role in cancer biology and potential implications for therapeutic interventions. This paper provides a novel understanding of the mechanisms by which these mutations contribute to the development of cancer.
肿瘤抑制蛋白p53（TP53）在包括头颈部鳞状细胞癌（HNSCC）在内的各种人类恶性肿瘤中经常发生突变，这会影响肿瘤生长、预后和治疗。深入了解TP53突变在HNSCC中的影响对于开发新的诊断和治疗方法至关重要。在本研究中，我们旨在通过计算分析研究突变对TP53蛋白结构和功能以及miRNA表达的影响。从癌症基因组图谱（TCGA）获取HNSCC患者的基因组数据，并使用不同的生物信息学工具研究突变对TP53基因的影响。结果：研究结果表明，TP53突变增加了HNSCC中TP53的表达水平，并与不良预后相关。此外，hsa - mir - 133b在TP53突变样本中的表达降低，显著影响HNSCC患者的生存。包括R273C、G105C、G266E、Q136H/P和R280G在内的六个突变被鉴定为有害、致癌、驱动、高度保守且暴露。这些突变位于P53结构域，蛋白质翻译后修饰（PTM）分析显示R280G和R273C位于甲基化位点，R273C、Q136H/P和R280G位于蛋白口袋中。对接研究表明这些突变降低了对DNA的结合亲和力，其中R273C、R280G、G266E和G105C表现出最显著的差异。分子动力学分析表明R280G、Q136H和G105C突变通过稳定TP53 - 底物复合物赋予功能获得。结论：基于研究结果，发现TP53突变对HNSCC患者的蛋白质和miRNA表达、发育、生存和进展有影响，并且hsa - mir - 133b可能是监测HNSCC进展的有前景的新型生物标志物。发现G105C和Q136H/P作为新突变影响导致HNSCC的蛋白质的功能和结构，这表明它们可能是进一步研究、诊断和治疗策略的有趣对象。此外，首次记录了R280G和R273C在甲基化位点内的精确定位以及Q136H/P在结合位点的定位。而且，稳定TP53结构并改变其与底物相互作用动力学的G105C、Q136H和R280G突变可能作为癌症中的新型潜在诊断生物标志物，指导患者分层和个性化治疗策略。分子动力学分析提供了关于特定TP53突变如何影响底物结合时蛋白质结构、稳定性和功能的见解，突出了它们在癌症生物学中的作用以及对治疗干预的潜在影响。本文对这些突变促成癌症发展的机制提供了新的理解。
