Dissecting the dynamics of dysregulation of cellular processes in mouse mammary gland tumor.
Dissecting the dynamics of dysregulation of cellular processes in mouse mammary gland tumor.
复制标题
解剖小鼠乳腺肿瘤中细胞过程失调的动力学。
DOI：
10.1186/1471-2164-10-601
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发表时间：
2009-12-13
期刊：
影响因子：
4.4
通讯作者：
de la Fuente A
中科院分区：
文献类型：
--
作者：
Mentzen WI;Floris M;de la Fuente A
阐明乳腺癌形成背后的分子事件序列对于了解这种疾病和设计有效的治疗方法具有巨大的价值。基因表达测量使得研究肿瘤发生中涉及的转录组范围的变化成为可能。这通常是通过识别差异表达的基因或途径来实现的。我们提出了一种新方法，能够描述新的癌症相关细胞过程及其参与肿瘤发生的性质。首先，我们将模块定义为蛋白质相互作用网络中紧密互连且功能丰富的区域。其次，“差异表达”和“差异共表达”分析应用于这些网络模块中的基因，从而可以识别上调或下调的过程，以及在不同肿瘤阶段被破坏（低共表达）或调用（高共表达）的过程。最后，我们提出了一种策略来识别可能对观察到的模块活动变化负责的调控 miRNA。我们证明了这种对来自乳腺肿瘤小鼠模型的表达数据进行分析的潜力，该模型对肿瘤发生的三个阶段进行了监测。研究发现，肿瘤细胞中富含粘附和代谢过程的网络模块通过失调和下调的组合而失活，而整合素复合物和免疫系统反应模块的激活是通过增加共调节和上调来实现的。此外，我们还证实了一种已知的 miRNA 参与乳腺肿瘤发生，并提出了该功能的几种新候选物。了解复杂的疾病需要通过结合数据源和不同分析方法的综合方法来研究它们。这里提出的方法和数据源的整合产生了一种敏感的工具，能够查明在癌症中发挥作用的新过程，剖析其活性的调节，并检测疾病过程中基因对功能模块的不同分配。
Elucidating the sequence of molecular events underlying breast cancer formation is of enormous value for understanding this disease and for design of an effective treatment. Gene expression measurements have enabled the study of transcriptome-wide changes involved in tumorigenesis. This usually occurs through identification of differentially expressed genes or pathways. We propose a novel approach that is able to delineate new cancer-related cellular processes and the nature of their involvement in tumorigenesis. First, we define modules as densely interconnected and functionally enriched areas of a Protein Interaction Network. Second, 'differential expression' and 'differential co-expression' analyses are applied to the genes in these network modules, allowing for identification of processes that are up- or down-regulated, as well as processes disrupted (low co-expression) or invoked (high co-expression) in different tumor stages. Finally, we propose a strategy to identify regulatory miRNAs potentially responsible for the observed changes in module activities. We demonstrate the potential of this analysis on expression data from a mouse model of mammary gland tumor, monitored over three stages of tumorigenesis. Network modules enriched in adhesion and metabolic processes were found to be inactivated in tumor cells through the combination of dysregulation and down-regulation, whereas the activation of the integrin complex and immune system response modules is achieved through increased co-regulation and up-regulation. Additionally, we confirmed a known miRNA involved in mammary gland tumorigenesis, and present several new candidates for this function. Understanding complex diseases requires studying them by integrative approaches that combine data sources and different analysis methods. The integration of methods and data sources proposed here yields a sensitive tool, able to pinpoint new processes with a role in cancer, dissect modulation of their activity and detect the varying assignments of genes to functional modules over the course of a disease.
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影响因子：
4.1
作者：
Crichton, MB;Nichols, JE;Simpson, ER
通讯作者：
Simpson, ER
影响因子：
11.2
作者：
Bracken, Cameron P.;Gregory, Philip A.;Goodall, Gregory J.
通讯作者：
Goodall, Gregory J.
Mirbase：MicroRNA基因组学的工具。
影响因子：
14.9
作者：
Griffiths-Jones, Sam;Saini, Harpreet Kaur;van Dongen, Stijn;Enright, Anton J.
通讯作者：
Enright, Anton J.
影响因子：
64.8
作者：
Hartwell, LH;Hopfield, JJ;Murray, AW
通讯作者：
Murray, AW
影响因子：
9.9
作者：
通讯作者：
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