胰岛素异常积累诱发转移性致癌通路激活的模型化研究

本文基于质量作用动力学与Michaelis-Menten方程建立理论模型，研究胰岛素异常积累诱发转移性致癌通路激活特性.理论模型考虑胰岛素通过激活PI3K-AKT-mTOR信号传导途径调控AKT-MDM2-P53-PTEN信号通路，以及胰岛素异常积累诱发JAK2/STAT5转移性致癌通路信号激活特性.研究发现，在JAK2/STAT5通路信号传导过程中，酪氨酸磷酸化的STAT5单体迅速转化为STAT5二聚体.随着异常胰岛素积累的增加，磷酸化的STAT5二聚体、酪氨酸磷酸化STAT5二聚体表达水平进一步提升.由此表明了，异常胰岛素积累诱发JAK2/STAT5转移性致癌通路激活.胰岛素异常积累通过直接提升JAK2的表达，导致了AKT的表达异常升高，致使细胞糖原代谢紊乱，P53蛋白抑癌作用降低，促进的癌症的发生发展. miR-378作为非常重要的抑癌因子，在JAK2/STAT5转移性致癌信号通路信号作用下，miR-378的抑癌效应被明显削弱，由此也表明了转移性癌症的复杂性.通过分析模型中各参数的敏感性，确定了JAK2/STAT5信号通路创设致癌微环境的灵敏性.本文理论结果符合实验理论观测，可为...

Modeling study on activation of metastatic carcinogenic pathway induced by abnormal accumulation of insulin

In this paper, based on mass action kinetics and Michaelis-Menten equation, we built a theoretical model to study the activation of metastatic carcinogenic pathways induced by abnormal accumulation of insulin. Theoretical model considers that insulin regulates the AKT-MDM2-P53-PTEN signaling pathway by activating the PI3K-AKT-mTOR signaling pathway, and the abnormal accumulation of insulin induces the activation of the JAK2/STAT5 metastatic carcinogenic pathway. We found that tyrosine phosphorylated STAT5 monomers are rapidly converted to STAT5 dimers during the signal transduction process of the JAK2/STAT5 pathway. As the abnormal accumulation of insulin increases, the expression levels of phosphorylated STAT5 dimers and tyrosine phosphorylated STAT5 dimers further increase. This indicates that abnormal insulin accumulation induces activation of the JAK2/STAT5 metastatic oncogenic pathway. Abnormal accumulation of insulin directly increases the expression of JAK2, which leads to an abnormal increase in the expression of AKT. It results in disorders of cellular glycogen metabolism. In the same time, the tumor suppressor effect of P53 protein reduces, promoting the occurrence and development of cancer. We also found, under the action of JAK2/STAT5 metastatic oncogenic signaling pathway, the tumor suppressor effect of miR-378 is significantly weakened, which also indicates the complexity of metastatic cancer. By analyzing the sensitivity of each parameter in the model, the sensitivity of the JAK2/STAT5 signaling pathway to create a carcinogenic microenvironment is determined. The theoretical results are consistent with the experiment, and can provide a reference for the design of treatment plans to inhibit metastatic cancer.