Corresponding Authors: Gang Zhao, Pancreatic Disease Institute, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Jiefang Avenue 1277, Wuhan, Hubei Province 430022, China.
Mol Cancer Ther. 2013 Nov;12(11):2569-80. doi: 10.1158/1535-7163.MCT-13-0296. Epub 2013 Sep 6.
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.
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。在这项研究中，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显著下调。此外，miR-141 水平的降低与肿瘤大小和 TNM 分期以及淋巴结和远处转移显著相关。同时，Kaplan-Meier 和多变量生存分析均表明，miR-141 降低与总生存率相关。在胰腺癌细胞中过表达 miR-141 可抑制细胞增殖、集落形成和侵袭；诱导 G1 期阻滞和细胞凋亡；并增强化疗敏感性。为了了解 miR-141 如何介导胰腺癌细胞的表型，使用生物信息学工具鉴定 MAP4K4 为 miR-141 的潜在靶标。双荧光素酶报告基因检测表明，miR-141 直接结合 MAP4K4 的 3'-非翻译区（3'UTR）以抑制 MAP4K4 表达。Western blot 和实时定量 PCR（qRT-PCR）分析显示，在胰腺癌样本和细胞系中，MAP4K4 的表达与 miR-141 的表达呈负相关。MAP4K4 的敲低抑制细胞增殖、集落形成和侵袭，诱导 G1 期阻滞和细胞凋亡，并增强化疗敏感性。在裸鼠异种移植模型中，miR-141 的过表达和 MAP4K4 的敲低均显著抑制胰腺癌细胞生长。因此，我们得出结论，miR-141 靶向 MAP4K4，作为胰腺癌细胞中的肿瘤抑制因子，可能成为 miRNA 为基础的胰腺癌治疗的新型治疗剂。
