MicroRNA-141, downregulated in pancreatic cancer, inhibited the cell proliferation and invasion by directly targeting MAP4K4
Menée sur des lignées cellulaires de cancer du pancréas et à l'aide de xénogreffes, cette étude met en évidence des mécanismes par lesquels, en interagissant avec le gène MAP4K4, le micro-ARN 141 joue un rôle de suppresseur de tumeurs
MicroRNAs (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 clinical characteristics analysis showed that miR-141 was significantly down-regulated in pancreatic cancer tissues and cell lines. Moreover, the decreased miR-141 was significantly associated with tumor size, TNM stage, lymph node and distant metastasis. Meanwhile, both Kaplan-Meier and multivariate survival analysis demonstrated 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 demonstrated that miR-141 binds directly to 3'UTR of MAP4K4 to inhibit MAP4K4 expression. Western blot and 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 nude mice 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 and acts as a tumor suppressor in pancreatic cancer cells, and may serve as a novel therapeutic agent for miRNA-based pancreatic cancer therapy.
http://mct.aacrjournals.org/content/early/2013/09/06/1535-7163.MCT-13-0296.abstract