Systematic analysis of metastasis-associated genes identifies miR-17-5p as a metastatic suppressor of basal-like breast cancer.
Systematic analysis of metastasis-associated genes identifies miR-17-5p as a metastatic suppressor of basal-like breast cancer.
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DOI：
10.1007/s10549-014-3040-5
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发表时间：
2014-08
影响因子：
3.8
通讯作者：
Pfeffer, Lawrence M.
中科院分区：
文献类型：
--
作者：
Fan, Meiyun;Sethuraman, Aarti;Brown, Martin;Sun, Wenlin;Pfeffer, Lawrence M.
本研究的目的是鉴定基底细胞样乳腺肿瘤转移相关基因/信号通路。Kaplan-Meier分析两个公开的元数据集和功能分类用于鉴定与无远处转移生存显著相关的基因/信号通路。mRNA和miRNA之间的表达相关性和相互作用的综合分析用于鉴定可能调节转移相关基因表达的miRNA。通过体外和体内实验检测miR-17- 5 p的新的转移抑制作用。研究人员检查了4,000多个先前与乳腺肿瘤进展相关的基因，分别鉴定出61个和69个与基底样肿瘤患者的DMFS间期缩短和延长显著相关的基因。功能注释将大多数促转移基因与上皮间质转化（EMT）过程和三条相互交织的EMT驱动途径（缺氧、TGFB和Wnt）联系起来，而大多数抗转移基因与干扰素信号通路联系起来。三个miRNA家族的成员（即，miR-17、miR-200和miR-96）被鉴定为促转移基因的潜在调节因子。通过体外和体内实验证实了miR-17- 5 p的新的抗转移功能。我们证明，乳腺癌细胞中的miR-17- 5 p抑制增强了多种促转移基因的表达，使细胞具有转移特性，并加速了原位异种移植物的肺转移。相比之下，肿瘤内施用miR-17- 5 p模拟物显著减少肺转移。这些结果提供证据支持EMT激活和IFN途径失活是基底细胞样肿瘤转移进展的标志物，并且miR-17、miR-200和miR-96家族的成员在抑制EMT和转移中起作用。在这项研究中发现的转移相关基因具有潜在的预后价值和功能意义，因此，可以利用作为治疗靶点，以防止转移的基底样乳腺肿瘤。
The purpose of this study is to identify metastasis- associated genes/signaling pathways in basal-like breast tumors. Kaplan–Meier analysis of two public meta-datasets and functional classification was used to identify genes/signaling pathways significantly associated with distant metastasis free survival. Integrated analysis of expression correlation and interaction between mRNAs and miRNAs was used to identify miRNAs that potentially regulate the expression of metastasis-associated genes. The novel metastatic suppressive role of miR-17-5p was examined by in vitro and in vivo experiments. Over 4,000 genes previously linked to breast tumor progression were examined, leading to identification of 61 and 69 genes significantly associated with shorter and longer DMFS intervals of patients with basal-like tumors, respectively. Functional annotation linked most of the pro-metastatic genes to epithelial mesenchymal transition (EMT) process and three intertwining EMT-driving pathways (hypoxia, TGFB and Wnt), whereas most of the anti-metastatic genes to interferon signaling pathway. Members of three miRNA families (i.e., miR-17, miR-200 and miR-96) were identified as potential regulators of the pro-metastatic genes. The novel anti-metastatic function of miR-17-5p was confirmed by in vitro and in vivo experiments. We demonstrated that miR-17-5p inhibition in breast cancer cells enhanced expression of multiple pro-metastatic genes, rendered cells metastatic properties, and accelerated lung metastasis from orthotopic xenografts. In contrast, intratumoral administration of miR-17-5p mimic significantly reduced lung metastasis. These results provide evidence supporting that EMT activation and IFN pathway inactivation are markers of metastatic progression of basal-like tumors, and members of miR-17, miR-200, and miR-96 families play a role in suppressing EMT and metastasis. The metastasis-associated genes identified in this study have potential prognostic values and functional implications, thus, can be exploited as therapeutic targets to prevent metastasis of basal-like breast tumors.
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影响因子：
5.8
作者：
Liberzon, Arthur;Subramanian, Aravind;Mesirov, Jill P.
通讯作者：
Mesirov, Jill P.
影响因子：
21.3
作者：
通讯作者：
--
系统筛选揭示显着调节四种主要信号通路的 MicroRNA 簇
影响因子：
3.7
作者：
Becker LE;Lu Z;Chen W;Xiong W;Kong M;Li Y
通讯作者：
Li Y
影响因子：
4.8
作者：
Macheda, Maria L.;Sun, Willy W.;Stacker, Steven A.
通讯作者：
Stacker, Steven A.
影响因子：
4.8
作者：
Fan, Meiyun;Krutilina, Raisa;Pfeffer, Lawrence M.
通讯作者：
Pfeffer, Lawrence M.