title: Overexpression of miR-199a-5p decreases esophageal cancer cell proliferation through repression of mitogen-activated protein kinase kinase kinase-11 (MAP3K11).
abstract: Studies examining the oncogenic or tumor suppressive functions of dysregulated microRNAs (miRs) in cancer cells may also identify novel miR targets, which can themselves serve as therapeutic targets. Using array analysis, we have previously determined that miR-199a-5p was the most downregulated miR in two esophageal cancer cell lines compared to esophageal epithelial cells. MiR-199a-5p is predicted to bind mitogen-activated protein kinase kinase kinase 11 (MAP3K11) mRNA with high affinity. In this study, we observed that MAP3K11 is markedly overexpressed in esophageal cancer cell lines. Forced expression of miR-199a-5p in these cells leads to a decrease in the mRNA and protein levels of MAP3K11, due to decreased MAP3K11 mRNA stability. A direct binding interaction between miR-199a-5p and MAP3K11 mRNA is demonstrated using biotin pull-down assays and heterologous luciferase reporter constructs and confirmed by mutational analysis. Finally, forced expression of miR-199a-5p decreases proliferation of esophageal cancer cells by inducing G2/M arrest. This effect is mediated, in part, by decreased transcription of cyclin D1, due to reduced MAP3K11-mediated phosphorylation of c-Jun. These findings suggest that miR-199a-5p acts as a tumor suppressor in esophageal cancer cells and that its downregulation contributes to enhanced cellular proliferation by targeting MAP3K11.
authors.affiliation: Department of Surgery, Cell Biology Group, University of Maryland School of Medicine, Baltimore, MD 21201, U.S.A.|Baltimore Veterans Affairs Medical Center, Baltimore, MD 21201, U.S.A.
authors.forename: Kimberly A
authors.initials: KA
authors.lastname: Byrnes
authors.affiliation: Department of Surgery, Cell Biology Group, University of Maryland School of Medicine, Baltimore, MD 21201, U.S.A.|Baltimore Veterans Affairs Medical Center, Baltimore, MD 21201, U.S.A.
authors.forename: Pornima
authors.initials: P
authors.lastname: Phatak
authors.affiliation: Department of Surgery, Cell Biology Group, University of Maryland School of Medicine, Baltimore, MD 21201, U.S.A.|Baltimore Veterans Affairs Medical Center, Baltimore, MD 21201, U.S.A.
authors.forename: Daniel
authors.initials: D
authors.lastname: Mansour
authors.affiliation: Department of Surgery, Cell Biology Group, University of Maryland School of Medicine, Baltimore, MD 21201, U.S.A.|Baltimore Veterans Affairs Medical Center, Baltimore, MD 21201, U.S.A.
authors.forename: Lan
authors.initials: L
authors.lastname: Xiao
authors.affiliation: Department of Surgery, Cell Biology Group, University of Maryland School of Medicine, Baltimore, MD 21201, U.S.A.|Baltimore Veterans Affairs Medical Center, Baltimore, MD 21201, U.S.A.
authors.forename: Tongtong
authors.initials: T
authors.lastname: Zou
authors.affiliation: Department of Surgery, Cell Biology Group, University of Maryland School of Medicine, Baltimore, MD 21201, U.S.A.|Baltimore Veterans Affairs Medical Center, Baltimore, MD 21201, U.S.A.
authors.forename: Jaladanki N
authors.initials: JN
authors.lastname: Rao
authors.affiliation: Department of Surgery, Cell Biology Group, University of Maryland School of Medicine, Baltimore, MD 21201, U.S.A.|Baltimore Veterans Affairs Medical Center, Baltimore, MD 21201, U.S.A.
authors.forename: Douglas J
authors.initials: DJ
authors.lastname: Turner
authors.affiliation: Department of Surgery, Cell Biology Group, University of Maryland School of Medicine, Baltimore, MD 21201, U.S.A.|Baltimore Veterans Affairs Medical Center, Baltimore, MD 21201, U.S.A.|Department of Pathology, University of Maryland School of Medicine, Baltimore, MD 21201, U.S.A.
authors.forename: Jian-Ying
authors.initials: JY
authors.lastname: Wang
authors.affiliation: Department of Surgery, Cell Biology Group, University of Maryland School of Medicine, Baltimore, MD 21201, U.S.A.|Baltimore Veterans Affairs Medical Center, Baltimore, MD 21201, U.S.A.
authors.forename: James M
authors.initials: JM
authors.lastname: Donahue
mesh_terms: D017209:Apoptosis; D015153:Blotting, Western; D002294:Carcinoma, Squamous Cell / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D002453:Cell Cycle; D049109:Cell Proliferation; D019295:Computational Biology; D004938:Esophageal Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D020930:MAP Kinase Kinase Kinases / Q000235:genetics / Q000378:metabolism*; D035683:MicroRNAs / Q000235:genetics*; D011401:Promoter Regions, Genetic / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014407:Tumor Cells, Cultured; D000097767:Mitogen-Activated Protein Kinase Kinase Kinase 11
chemical_list: D020930:MAP Kinase Kinase Kinases; D035683:MicroRNAs; D012333:RNA, Messenger; D000097767:Mitogen-Activated Protein Kinase Kinase Kinase 11; C531408:mirn199 microRNA, human
keywords: MAP3K11; esophageal cancer; mRNA stability; miR-199a-5p; proliferation