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Abstract
Mature microRNAs (miRNAs) are 21 to 23 nucleotide noncoding RNA molecules that can downregulate multiple gene expression by mRNA degradation or translational repression. miRNAs are considered to play important roles in cell proliferation, apoptosis, and differentiation during mammalian development. The Runt-related transcription factor 3 (RUNX3) expression and activity are frequently downregulated by various mechanisms in gastric cancer. We have reported that RUNX3 inactivation is crucial for early tumorigenesis. In this study, we investigated the role of miRNAs targeting RUNX3 in early tumorigenesis. miR-130a and miR-495 upregulated under hypoxic conditions that bind to the RUNX3 3'-untranslated region (3'-UTR) were identified in gastric cancer cells by using microarray analysis and bioinformatics programs. Combination of miR-130a and miR-495 inhibited RUNX3 expression at the protein level, but not at the mRNA level. miR-130a and miR-495 significantly inhibited the RUNX3-3'UTR-luciferase activity. Combination of miR-130a and miR-495 significantly decreased apoptosis determined by Annexin V-FITC/propidium iodide staining and flow cytometric analysis, and the expression of Bim in SNU484 gastric cancer cells. In addition, p21 and Bim, RUNX3 target genes, were completely downregulated by the combination of miR-130a and miR-495. Using matrigel plug assay, we found that antagomiRs specific for miR-130a and miR-495 significantly reduced angiogenesis in vivo. In conclusion, targeting miR-130a and miR-495 could be a potential therapeutics to recover RUNX3 expression under hypoxic conditions and in early tumorigenic progression.
Highlights
MicroRNAs are 21–23 nucleotide RNA molecules that modulate the stability or translational efficiency of target messenger RNAs [1, 2]
The biogenesis of miRNAs begins with a primary transcript, termed the pri-miRNA, and the combined action of Drosha and Dicer ribonucleases generates the mature miRNA species [3]. miRNAs binding to 3′-untranslated region (UTR) of the targeted mRNA leads to its degradation or translational repression [4]. miRNAs regulate a variety of biological processes, including cellular differentiation, proliferation, metabolic signaling, and apoptosis [4]
In specific gastric cancer cells such as SNU5 and SNU484 cells, RUNX3 mRNA expression was not decreased, but its protein level was reduced under hypoxic conditions (Figure 1A)
Summary
MicroRNAs (miRNAs) are 21–23 nucleotide RNA molecules that modulate the stability or translational efficiency of target messenger RNAs [1, 2]. MiRNAs regulate a variety of biological processes, including cellular differentiation, proliferation, metabolic signaling, and apoptosis [4]. Differential expression of miRNAs between normal and tumor tissues has been observed in various cancer types, suggesting a possible link between miRNA expression and the development of cancer [5]. Deregulated miRNAs may function as tumor suppressors such as miR-205 and let-7 [6, 7], or oncogenes such as miR-17–92 cluster and miR214 [8, 9], depending on the regulated targets. We proposed that deregulation of candidate miRNAs could be a possible mechanism for the downregulation of tumor suppressors in tumors. RUNX3 is related to neurogenesis of the dorsal root ganglia, T-cell differentiation, and tumorigenesis of the gastric epithelium. Primary gastric cancer specimens express lower levels of www.impactjournals.com/oncotarget
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