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.
Highlights
Esophageal cancer is the 6th leading cause of cancer-related death in the world [1]
In support of this hypothesis, we found that baseline levels of MAP3K11 are elevated in TE7 and TE10 cells in comparison to human esophageal epithelial cell line (hESO) cells (Figure 1B)
Our findings indicate that miR-199a-5p is markedly downregulated in esophageal squamous cancer cell lines compared to esophageal epithelial cells
Summary
Esophageal cancer is the 6th leading cause of cancer-related death in the world [1]. Given the rising prevalence of this deadly disease, increased efforts aimed at understanding the molecular mechanisms underlying the development and progression of esophageal cancer are urgently required. Such efforts are needed to develop predictive and prognostic biomarkers as well as to identify candidates for targeted therapies. MicroRNAs (miRs) are well recognized as critical post-transcriptional regulators of gene expression in cancer cells [3]. Individual miRs can modulate multiple biologic processes based on their ability to target several distinct transcripts [4]. The particular role played by an individual miR may differ depending on the specific malignant cell type
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