Lu Yulin, Wang Danjun, Chen Guoao, Shan Zitong, Li Dongmei
School of Medicine, Shihezi University, Shihezi, Xinjiang, China.
Key Laboratory of Xinjiang Endemic and Ethnic Diseases, School of Medicine, Shihezi University, Shihezi, Xinjiang, China.
Front Genet. 2024 Jul 30;15:1431668. doi: 10.3389/fgene.2024.1431668. eCollection 2024.
Osteosarcoma (OS) poses a significant clinical challenge, necessitating a comprehensive exploration of its molecular underpinnings.
This study explored the roles of PTTG family genes (PTTG1, PTTG2, and PTTG3P) in OS, employing a multifaceted approach encompassing molecular experiments, including OS cell lines culturing, RT-qPCR, bisulfite and Whole Exome Sequencing (WES) and experiments, including The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) datasets-based validation, overall survival, gene enrichment, functional assays, and molecular docking analyses.
Our findings reveal a consistent up-regulation of PTTG genes in OS cell lines, supported by RT-qPCR experiments and corroborated across various publically available expression datasets databases. Importantly, ROC curve analyses highlight their potential as diagnostic markers. Moving beyond expression profiles, we unveil the epigenetic landscape by demonstrating significant hypomethylation of CpG islands associated with PTTG genes in OS. The negative correlation between methylation status and mRNA expression emphasizes the regulatory role of promoter methylation in PTTG gene expression. Contrary to expectations, genetic mutations in PTTG genes are rare in OS, with only benign mutations observed. Moreover, functional assays also confirmed the oncogenic roles of the PTTG gene in the development of OS. Lastly, we also revealed that Calcitriol is the most appropriate drug that can be utilized to treat OS in the context of PTTG genes.
The identification of PTTG genes as potential diagnostic markers and their association with epigenetic alterations opens new avenues for understanding OS pathogenesis and developing targeted therapies. As we navigate the complex landscape of OS, this study contributes essential insights that may pave the way for improved diagnostic and therapeutic strategies in its management.
骨肉瘤（OS）带来了重大的临床挑战，需要对其分子基础进行全面探索。
本研究采用多方面方法探讨PTTG家族基因（PTTG1、PTTG2和PTTG3P）在骨肉瘤中的作用，包括分子实验，如骨肉瘤细胞系培养、RT-qPCR、亚硫酸氢盐和全外显子测序（WES），以及实验，如基于癌症基因组图谱（TCGA）和基因表达综合数据库（GEO）数据集的验证、总生存期、基因富集、功能测定和分子对接分析。
我们的研究结果显示，骨肉瘤细胞系中PTTG基因持续上调，这得到了RT-qPCR实验的支持，并在各种公开可用的表达数据集数据库中得到证实。重要的是，ROC曲线分析突出了它们作为诊断标志物的潜力。除了表达谱，我们通过证明骨肉瘤中与PTTG基因相关的CpG岛显著低甲基化，揭示了表观遗传格局。甲基化状态与mRNA表达之间的负相关强调了启动子甲基化在PTTG基因表达中的调节作用。与预期相反，骨肉瘤中PTTG基因的基因突变很少见，仅观察到良性突变。此外，功能测定也证实了PTTG基因在骨肉瘤发生发展中的致癌作用。最后，我们还发现骨化三醇是在PTTG基因背景下可用于治疗骨肉瘤的最合适药物。
将PTTG基因鉴定为潜在的诊断标志物及其与表观遗传改变的关联，为理解骨肉瘤发病机制和开发靶向治疗开辟了新途径。在我们探索骨肉瘤的复杂格局时，本研究提供了重要见解，可能为其管理中改进诊断和治疗策略铺平道路。
