miRNA Alterations Modify Kinase Activation In The IGF-1 Pathway And Correlate With Colorectal Cancer Stage And Progression In Patients
miRNA Alterations Modify Kinase Activation In The IGF-1 Pathway And Correlate With Colorectal Cancer Stage And Progression In Patients
复制标题
DOI：
10.7150/jca.2.490
复制
发表时间：
2011-01-01
影响因子：
3.9
通讯作者：
Subramanian, Romesh R.
中科院分区：
文献类型：
--
作者：
Knowlton, David L.;Tang, Kim;Subramanian, Romesh R.
对未经治疗的人类肿瘤和邻近正常组织活检的研究表明，miRNA的表达水平在CRC阶段和阶段之间发生变化。这些改变的miRNA的靶点是胰岛素信号通路的成员。胰岛素信号通路中的几种分子的磷酸化状态在CRC的不同阶段之间发生了改变，并且分子磷酸化状态的变化与靶向它们的特定miRNA的减少显著相关。这些数据建立了IGF-1通路中特定miRNAs表达减少和磷酸化事件增加之间的直接关系，并将IGF-1通路确定为结直肠癌的关键驱动因素。有趣的是，我们观察到miRNA的表达发生了改变，几种信号分子的磷酸化水平在CRC的各个阶段和阶段之间发生了改变。此外，在每个CRC阶段差异表达的许多miRNA靶向这些被鉴定为磷酸化水平改变的相同信号蛋白。因此，我们的研究定义了一个重要的miRNA子集，以分类CRC阶段和miRNA抑制与IGF-1 R通路信号分子磷酸化水平升高之间的关系。
Investigation of therapy naive human tumor and adjacent normal tissue biopsies demonstrated that expression levels of miRNAs are altered at and between stages of CRC. Targets of these altered miRNAs are members of the Insulin signaling pathways. Phosphorylation states of several molecules in the Insulin signaling pathways were altered between stages of CRC, and significantly the change in molecular phosphorylation state correlated with decreases in specific miRNAs that target them. This data establishes a direct relationship between decreased expression of specific miRNAs and increased phosphorylation events in the IGF-1 pathway and identifies the IGF-1 pathway as a critical driver of colorectal cancer.The expression levels of 319 miRNAs and phosphorylation levels of major signaling proteins were determined. Interestingly, we observed that miRNAs were altered in expression and several signaling molecules were altered in phosphorylation levels at and between each stage of CRC. Furthermore, many of the miRNAs that are differentially expressed at each CRC stage were targeting these same signaling proteins identified to be altered in phosphorylation level. Thus, our studies define a subset of important miRNAs to classify CRC stage and a relationship between miRNA depression and elevated phosphorylation of IGF-1R pathway signaling molecules.