A mathematical model for microRNA in lung cancer.
A mathematical model for microRNA in lung cancer.
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DOI：
10.1371/journal.pone.0053663
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Friedman A
中科院分区：
文献类型：
--
作者：
Kang HW;Crawford M;Fabbri M;Nuovo G;Garofalo M;Nana-Sinkam SP;Friedman A
肺癌是全球癌症相关死亡的主要原因。缺乏早期检测和靶向治疗的选择有限都是肺癌中观察到的令人沮丧的统计数据的促成因素。因此，这两个领域的进展可能会导致更好的结果。microRNA（miRs或miRNAs）代表一类具有基因调控能力的非编码RNA，并且可以用作肺癌的诊断和预后生物标志物。已经在肺癌中鉴定了几种miRNA的异常表达模式。具体而言，let-7和miR-9在肺癌和其他实体恶性肿瘤中都是失调的。在本文中，我们构建了一个数学模型，将let-7和miR-9表达整合到一个信号通路中，以生成上皮间质转化（EMT）过程的计算机模型。该模型的模拟表明，非小细胞肺癌（NSCLC）中的EGFR和Ras突变导致EMT过程，导致miR-9上调和let-7抑制，并且该过程对miR-9的随机输入具有一定的鲁棒性，对let-7的随机输入具有更强的鲁棒性。我们选择通过测试EGFR抑制对下游MYC、miR-9和let-7a表达的影响来验证我们的体外模型。有趣的是，在EGFR突变的肺癌细胞系中，用EGFR抑制剂（吉非替尼）处理导致c-MYC和miR-9表达的浓度特异性降低，而不改变let-7a表达。我们的数学模型解释了EGFR，MYC和miR-9之间的信号联系，但不是let-7。然而，目前对调节let-7的因素知之甚少。很有可能，当这些调节因素变得已知并整合到我们的模型中时，它们将进一步支持我们的数学模型。
Lung cancer is the leading cause of cancer-related deaths worldwide. Lack of early detection and limited options for targeted therapies are both contributing factors to the dismal statistics observed in lung cancer. Thus, advances in both of these areas are likely to lead to improved outcomes. MicroRNAs (miRs or miRNAs) represent a class of non-coding RNAs that have the capacity for gene regulation and may serve as both diagnostic and prognostic biomarkers in lung cancer. Abnormal expression patterns for several miRNAs have been identified in lung cancers. Specifically, let-7 and miR-9 are deregulated in both lung cancers and other solid malignancies. In this paper, we construct a mathematical model that integrates let-7 and miR-9 expression into a signaling pathway to generate an in silico model for the process of epithelial mesenchymal transition (EMT). Simulations of the model demonstrate that EGFR and Ras mutations in non-small cell lung cancers (NSCLC), which lead to the process of EMT, result in miR-9 upregulation and let-7 suppression, and this process is somewhat robust against random input into miR-9 and more strongly robust against random input into let-7. We elected to validate our model in vitro by testing the effects of EGFR inhibition on downstream MYC, miR-9 and let-7a expression. Interestingly, in an EGFR mutated lung cancer cell line, treatment with an EGFR inhibitor (Gefitinib) resulted in a concentration specific reduction in c-MYC and miR-9 expression while not changing let-7a expression. Our mathematical model explains the signaling link among EGFR, MYC, and miR-9, but not let-7. However, very little is presently known about factors that regulate let-7. It is quite possible that when such regulating factors become known and integrated into our model, they will further support our mathematical model.
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影响因子：
3.3
作者：
Hopkins, Susan R.;Henderson, A. Cortney;Prisk, G. Kim
通讯作者：
Prisk, G. Kim
影响因子：
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作者：
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影响因子：
21.3
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通讯作者：
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影响因子：
4.8
作者：
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通讯作者：
Matsuda, M
影响因子：
1.2
作者：
Chaplain, Mark A. J.
通讯作者：
Chaplain, Mark A. J.