miRNA-141, Downregulated in Pancreatic Cancer, Inhibits Cell Proliferation and Invasion by Directly Targeting MAP4K4
miRNA-141, Downregulated in Pancreatic Cancer, Inhibits Cell Proliferation and Invasion by Directly Targeting MAP4K4
复制标题
miRNA-141 在胰腺癌中下调，通过直接靶向 MAP4K4 抑制细胞增殖和侵袭
DOI：
10.1158/1535-7163.mct-13-0296
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发表时间：
2013-11-01
影响因子：
5.7
通讯作者：
Wang, Chun-you
中科院分区：
文献类型：
--
作者：
Zhao, Gang;Wang, Bo;Wang, Chun-you
MiRNAs与各种类型的癌症有关，因为它们能够影响调节肿瘤发生的基因的表达。在本研究中，我们探讨了miR-141在胰腺癌中的作用。临床特征分析表明，miR-141在胰腺癌组织和细胞系中表达明显下调。此外，miR-141水平降低与肿瘤大小、TNM分期、淋巴结转移及远处转移显著相关。同时，Kaplan-Meier生存分析和多因素生存分析均显示miR-141表达降低与总生存期相关。在胰腺癌细胞中过表达miR-141抑制了细胞的增殖、克隆形成和侵袭，诱导了G1期停滞和凋亡，并增强了对化疗的敏感性。为了了解miR-141如何介导胰腺癌细胞的表型，利用生物信息学工具将MAP4K4确定为miR-141的潜在靶点。双荧光素酶报告基因分析表明，miR-141直接与MAP4K4的3‘非翻译区(3’UTR)结合，抑制MAP4K4的表达。Western印迹和实时定量聚合酶链式反应(qRT-PCR)分析显示，MAP4K4和miR-141在胰腺癌组织和细胞系中的表达呈负相关。MAP4K4基因的敲除抑制了细胞的增殖、克隆形成和侵袭，诱导了G1期的停滞和凋亡，并增强了化疗的敏感性。在裸鼠异种移植模型中，miR-141的过表达和MAP4K4的下调都显著抑制了胰腺癌细胞的生长。因此，我们得出结论，miR-141靶向MAP4K4，在胰腺癌细胞中发挥肿瘤抑制作用，可能成为基于miRNA的胰腺癌治疗的一种新的治疗药物。摩尔癌症治疗；12(11)；2569-80。©2013 AACR。
miRNAs are associated with various types of cancer due to their ability to affect expression of genes that modulate tumorigenesis. In this study, we explored the role of miR-141 in pancreatic cancer. The analysis of clinical characteristics showed that miR-141 was significantly downregulated in tissues and cell lines of pancreatic cancer. Moreover, the decreased miR-141 level was significantly associated with tumor size and TNM stage, as well as lymph node and distant metastasis. Meanwhile, both Kaplan–Meier and multivariate survival analysis showed decreased miR-141 were associated with overall survival. Overexpression of miR-141 in pancreatic cancer cells inhibited cell proliferation, clonogenicity, and invasion; induced G1 arrest and apoptosis; and enhanced chemosensitivity. To understand how miR-141 mediates the phenotype of pancreatic cancer cells, a bioinformatics tool was used to identify MAP4K4 as a potential target of miR-141. The Dual-Luciferase reporter gene assay showed that miR-141 binds directly to the 3′-untranslated region (3′UTR) of MAP4K4 to inhibit MAP4K4 expression. Western blot and quantitative real-time PCR (qRT-PCR) analyses revealed that MAP4K4 expression was inversely correlated with miR-141 expression both in pancreatic cancer samples and cell lines. Knockdown of MAP4K4 inhibited cell proliferation, clonogenicity, and invasion, induced G1 arrest and apoptosis, and enhanced chemosensitivity. In a nude mouse xenograft model, both overexpression of miR-141 and knockdown of MAP4K4 significantly repressed pancreatic cancer cell growth. Therefore, we conclude that miR-141 targets MAP4K4, acts as a tumor suppressor in pancreatic cancer cells, and may serve as a novel therapeutic agent for miRNA-based pancreatic cancer therapy. Mol Cancer Ther; 12(11); 2569–80. ©2013 AACR.