Suescum-Holguín Jeison F, Clavijo-Buriticá Diana Carolina, Carrillo-Borda Edward Fabian, Quimbaya Mauricio Alberto
Facultad de Ingeniería y Ciencias, Instituto de Investigaciones en Ciencias Ómicas iÓMICAS, Pontificia Universidad Javeriana Cali, Santiago de Cali 760031, Colombia.
Grupo de Investigación en Microbiología Molecular y Enfermedades Infecciosas (GIMMEIN), Faculty of Health Sciences, Universidad Libre Seccional Cali, Santiago de Cali 760043, Colombia.
Life (Basel). 2025 May 17;15(5):799. doi: 10.3390/life15050799.
Genomic instability has been increasingly recognized over the past decade as a fundamental driver of cancer initiation and progression, largely owing to its association with specific genes and cellular mechanisms that offer therapeutic potential. However, a comprehensive molecular framework that captures the interconnected processes underlying this phenomenon remains elusive. In this study, we focused on polo-like kinase 1 (PLK1), a key cell cycle regulator frequently overexpressed in diverse human tumors, to reconstruct a regulatory network that consolidates pre-existing biological knowledge exclusively related to pathways involved in genome stability maintenance and cancer. The resulting model integrates nine biological processes, 1030 reactions, and 716 molecular species to form a literature-supported network in which PLK1 serves as a central regulatory node. However, rather than depicting an isolated PLK1-centric system, this network reflects a broader and more complex architecture of interrelated genomic instability mechanisms. As expected, the simulations reproduced known behaviors associated with PLK1 dysregulation, reinforcing the well-established role of the kinase in genome destabilization. Importantly, this model also enables the exploration of additional, less-characterized dynamics, including the potential involvement of genes such as , , and other regulators of chromosomal segregation and DNA repair, which appear to contribute to instability events downstream of PLK1. While these findings are grounded in mechanistic simulations and require further experimental validation, gene expression and survival analyses across tumor types support their clinical relevance by linking them to poor prognosis in specific cancers. Overall, the model provides a systemic and adaptable foundation for studying PLK1-related genomic instability, enabling both the reinforcement of known mechanisms and discovery of candidate genes and circuits that may drive tumorigenesis through compromised genome integrity across distinct cancer contexts.
在过去十年中，基因组不稳定已日益被视为癌症发生和发展的一个基本驱动因素，这主要归因于它与具有治疗潜力的特定基因和细胞机制相关联。然而，一个能够捕捉这一现象背后相互关联过程的全面分子框架仍然难以捉摸。在本研究中，我们聚焦于波罗样激酶1（PLK1），一种在多种人类肿瘤中经常过度表达的关键细胞周期调节因子，以重建一个调控网络，该网络整合了仅与参与基因组稳定性维持和癌症的途径相关的现有生物学知识。由此产生的模型整合了九个生物学过程、1030个反应和716个分子物种，形成了一个有文献支持的网络，其中PLK1作为核心调控节点。然而，这个网络并非描绘一个孤立的以PLK1为中心的系统，而是反映了相互关联的基因组不稳定机制的更广泛、更复杂的架构。正如预期的那样，模拟重现了与PLK1失调相关的已知行为，强化了该激酶在基因组不稳定中的既定作用。重要的是，这个模型还能够探索其他特征较少的动态，包括诸如、和其他染色体分离及DNA修复调节因子等基因的潜在参与，这些基因似乎在PLK1下游的不稳定事件中起作用。虽然这些发现基于机制模拟且需要进一步的实验验证，但跨肿瘤类型的基因表达和生存分析通过将它们与特定癌症的不良预后联系起来，支持了它们的临床相关性。总体而言，该模型为研究与PLK1相关的基因组不稳定提供了一个系统且可适应的基础，可以强化已知机制，并发现可能通过不同癌症背景下受损的基因组完整性驱动肿瘤发生的候选基因和回路。
