Overexpression of miR-199a-5p decreases esophageal cancer cell proliferation through repression of mitogen-activated protein kinase kinase kinase-11 (MAP3K11)
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Kimberly A. Byrnes1,2, Pornima Phatak1,2, Daniel Mansour1,2, Lan Xiao1,2, Tongtong Zou1,2, Jaladanki N. Rao1,2, Douglas J. Turner1,2, Jian-Ying Wang1,2,3, James M. Donahue1,2
1Department of Surgery, Cell Biology Group, University of Maryland School of Medicine, Baltimore, MD 21201, U.S.A
2Baltimore Veterans Affairs Medical Center, Baltimore, MD 21201, U.S.A
3Department of Pathology, University of Maryland School of Medicine, Baltimore, MD 21201, U.S.A
James M. Donahue, e-mail: email@example.com
Keywords: miR-199a-5p, MAP3K11, esophageal cancer, mRNA stability, proliferation
Received: August 08, 2015 Accepted: November 16, 2015 Published: December 24, 2015
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.
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