Aguda Baltazar D, del Rosario Ricardo C H, Chan Michael W Y
DiseasePathways LLC, Bethesda, Maryland, 20814, United States. email:
Math Biosci Eng. 2015 Dec;12(6):1277-88. doi: 10.3934/mbe.2015.12.1277.
We propose the hypothesis that for a particular type of cancer there exists a key pair of oncogene (OCG) and tumor suppressor gene (TSG) that is normally involved in strong stabilizing negative feedback loops (nFBLs) of molecular interactions, and it is these interactions that are sufficiently perturbed during cancer development. These nFBLs are thought to regulate oncogenic positive feedback loops (pFBLs) that are often required for the normal cellular functions of oncogenes. Examples given in this paper are the pairs of MYC and p53, KRAS and INK4A, and E2F1 and miR-17-92. We propose dynamical models of the aforementioned OCG-TSG interactions and derive stability conditions of the steady states in terms of strengths of cycles in the qualitative interaction network. Although these conditions are restricted to predictions of local stability, their simple linear expressions in terms of competing nFBLs and pFBLs make them intuitive and practical guides for experimentalists aiming to discover drug targets and stabilize cancer networks.
我们提出一个假设，即对于某一特定类型的癌症，存在一对关键的原癌基因（OCG）和肿瘤抑制基因（TSG），它们通常参与分子相互作用的强稳定负反馈回路（nFBLs），而正是这些相互作用在癌症发展过程中受到了足够的干扰。这些nFBLs被认为调控着原癌基因正常细胞功能通常所需的致癌正反馈回路（pFBLs）。本文给出的例子是MYC和p53、KRAS和INK4A以及E2F1和miR-17-92这几对基因。我们提出上述OCG-TSG相互作用的动力学模型，并根据定性相互作用网络中循环的强度推导出稳态的稳定性条件。尽管这些条件仅限于局部稳定性的预测，但它们基于相互竞争的nFBLs和pFBLs的简单线性表达式，使其成为旨在发现药物靶点并稳定癌症网络的实验人员直观且实用的指导。
