title: miRNA-141, downregulated in pancreatic cancer, inhibits cell proliferation and invasion by directly targeting MAP4K4.
abstract: 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.
authors.affiliation: 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. gangzhao@aliyun.com.
authors.forename: Gang
authors.initials: G
authors.lastname: Zhao
authors.forename: Bo
authors.initials: B
authors.lastname: Wang
authors.forename: Yang
authors.initials: Y
authors.lastname: Liu
authors.forename: Jun-Gang
authors.initials: JG
authors.lastname: Zhang
authors.forename: Shi-Chang
authors.initials: SC
authors.lastname: Deng
authors.forename: Qi
authors.initials: Q
authors.lastname: Qin
authors.forename: Kui
authors.initials: K
authors.lastname: Tian
authors.forename: Xiang
authors.initials: X
authors.lastname: Li
authors.forename: Shuai
authors.initials: S
authors.lastname: Zhu
authors.forename: Yi
authors.initials: Y
authors.lastname: Niu
authors.forename: Qiong
authors.initials: Q
authors.lastname: Gong
authors.forename: Chun-You
authors.initials: CY
authors.lastname: Wang
mesh_terms: D020413:3' Untranslated Regions; D000328:Adult; D000368:Aged; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D055785:Gene Knockdown Techniques; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D008819:Mice, Nude; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D008875:Middle Aged; D058990:Molecular Targeted Therapy; D009361:Neoplasm Invasiveness; D010190:Pancreatic Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D023041:Xenograft Model Antitumor Assays
chemical_list: D020413:3' Untranslated Regions; D047908:Intracellular Signaling Peptides and Proteins; C533895:MIRN141 microRNA, human; D035683:MicroRNAs; C117090:MAP4K4 protein, human; D017346:Protein Serine-Threonine Kinases