The State Key Laboratory for Artificial Microstructures and Mesoscopic Physics, Department of Physics, Peking University, Beijing, China.
College of Mathematics and Compute Science, Hunan Normal University, Changsha, China.
PLoS One. 2018 Jun 18;13(6):e0198579. doi: 10.1371/journal.pone.0198579. eCollection 2018.
Understanding how gene alterations induce oncogenesis plays an important role in cancer research and may be instructive for cancer prevention and treatment. We conducted a parameter sensitivity analysis to the mitochondrial apoptosis model. Both a nonlinear bifurcation analysis of the deterministic dynamics and energy barrier analysis of the corresponding stochastic models were performed. We found that the parameter sensitivity ranking according to the change of the bifurcation-point locations in deterministic models and the change of the barrier heights from a living to death state of the cell in stochastic models are highly correlated. For the model we considered, in combination with previous knowledge that the parameters significantly affecting the system's bifurcation point are strongly associated with frequently mutated oncogenic genes, we conclude that the energy barrier height can be used as indicator of oncogenesis as well as bifurcation point. We provide a possible mechanism that may help elucidate the logic of cancer initiation from the view of stochastic dynamics and energy landscape. And we show the equivalence of energy barrier height and bifurcation-point location in determining the parameter sensitivity spectrum for the first time.
了解基因改变如何诱导肿瘤发生在癌症研究中起着重要作用，并且可能对癌症的预防和治疗具有指导意义。我们对线粒体凋亡模型进行了参数敏感性分析。对确定性动力学进行了非线性分岔分析，对相应的随机模型进行了能量势垒分析。我们发现，根据确定性模型中分叉点位置的变化和随机模型中细胞从存活状态到死亡状态的势垒高度的变化，参数敏感性排序具有高度相关性。对于我们所考虑的模型，结合先前的知识，即显著影响系统分叉点的参数与经常发生突变的致癌基因密切相关，我们得出结论，能量势垒高度可以作为肿瘤发生的指标，也可以作为分叉点的指标。我们提供了一种可能的机制，从随机动力学和能量景观的角度可以帮助阐明癌症发生的逻辑。并且我们首次表明，在确定参数敏感性谱方面，能量势垒高度和分叉点位置是等效的。
