MicroRNAs Associated with Mitogen-Activated Protein Kinase in Human Pancreatic Cancer
MicroRNAs Associated with Mitogen-Activated Protein Kinase in Human Pancreatic Cancer
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DOI：
10.1158/1541-7786.mcr-11-0035
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发表时间：
2012-02-01
影响因子：
5.2
通讯作者：
Furukawa, Toru
中科院分区：
文献类型：
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作者：
Ikeda, Yushi;Tanji, Etsuko;Furukawa, Toru
MicroRNAs(MiRNA)的异常表达与包括胰腺癌在内的多种癌症的表型有关。然而，这种异常表达的机制在很大程度上还不清楚。丝裂原活化蛋白激酶(MAPK)信号通路的激活在胰腺癌恶性表型相关基因表达中起着至关重要的作用。因此，我们研究了MAPK在胰腺癌细胞miRNAs异常表达中的作用。采用实时荧光定量聚合酶链式反应方法，检测MAPK激活或失活对体外培养的胰腺癌细胞和HEK293细胞中183个miRNAs表达的影响。我们发现四个miRNAs，即miR-7-3、miR-34a、miR-181d和miR-193B优先与MAPK活性相关。在这些miRNAs中，miR-7-3被激活的MAPK上调，而其他miRNAs下调。启动子分析表明，MAPK活性的改变下调了宿主基因miR-7-3和miR-34a的启动子活性。外源性MAPK相关miRNAs的过表达对胰腺癌细胞的增殖有抑制作用，其中miR-193B的抑制作用最为明显。对miR-193B的靶基因进行搜索，确定CCND1、NT5E、PLAU、STARD7、STMN1和YWHAZ为靶基因。报告实验证实miR-193B对这些基因的翻译抑制作用。这些结果表明，MAPK的激活可能在胰腺癌miRNAs及其相关表型的异常表达中起重要作用。摩尔癌症资源；10(2)；259-69。(C)2011年AACR。
Aberrant expression of microRNAs (miRNA) is associated with phenotypes of various cancers, including pancreatic cancer. However, the mechanism of the aberrant expression is largely unknown. Activation of the mitogen-activated protein kinase (MAPK) signaling pathway plays a crucial role in gene expression related to the malignant phenotype of pancreatic cancer. Hence, we studied the role of MAPK in the aberrant expression of miRNAs in pancreatic cancer cells. The alterations in expression of 183 miRNAs induced by activation or inactivation of MAPK were assayed in cultured pancreatic cancer cells and HEK293 cells by means of the quantitative real-time PCR method. We found that four miRNAs, namely, miR-7-3, miR-34a, miR-181d, and miR-193b, were preferentially associated with MAPK activity. Among these miRNAs, miR-7-3 was upregulated by active MAPK, whereas the others were downregulated. Promoter assays indicated that the promoter activities of the host genes of miR-7-3 and miR-34a were both downregulated by alteration in MAPK activity. Exogenous overexpression of the MAPK-associated miRNAs had the effect of inhibition of the proliferation of cultured pancreatic cancer cells; miR-193b was found to exhibit the most remarkable inhibition. A search for target genes of miR-193b led to identification of CCND1, NT5E, PLAU, STARD7, STMN1, and YWHAZ as the targets. Translational suppression of these genes by miR-193b was confirmed by reporter assay. These results indicate that activation of MAPK may play a significant role in aberrant expression of miRNAs and their associated phenotypes in pancreatic cancer. Mol Cancer Res; 10(2); 259-69. (C)2011 AACR.