Abstract
MIR17HG, located on chromosome 13, is a class of Pri-miRNAs that generates six miRNAs: miR-17, miR-18a, miR-19a, miR-20a, miR-19b-1 and miR-92-1. These miRNAs are ubiquitously overexpressed in diverse tumour types and exhibit complex biological links to tumour metastasis. We demonstrated that MIR17HG-derived miR-18a and miR-19a coordinately mediate gastric cancer cell metastasis by directly inhibiting SMAD2 expression and upregulating Wnt/β-catenin signalling. Based on previous studies, we hypothesised that an investigation of MIR17HG inhibition would be beneficial to clinical gastric cancer treatment, and systematically coupled bioinformatics analyses brought interferon regulatory factor-1 (IRF-1) to our attention. We then established stable clones in gastric cancer cells containing a doxycycline-inducible IRF-1 expression system and found that the expression of IRF-1 downregulates the embedded miRNAs of MIR17HG in gastric cancer cells and inhibits gastric cancer cell metastasis by attenuating Wnt/β-catenin signalling. Further rescue assays confirmed the crucial roles of miR-18a and miR-19a in the IRF-1-mediated inhibition of Wnt/β-catenin signalling. We also demonstrated that IRF-1 binds to the transcriptional site in the MIR17HG promoter and inhibits MIR17HG expression. Moreover, IFN-γ induced the IRF-1-mediated downregulation of MIR17HG in gastric cancer cells. Our hypothesis was supported by the results of immunohistochemistry analyses of clinical gastric cancer samples, and we also demonstrated the role of IRF-1 in inhibiting MIR17HG expression and tumour metastasis in vivo. We conclude that IRF-1 inhibits gastric cancer metastasis by downregulating MIR17HG-miR-18a/miR-19a axis expression and attenuating Wnt/β-catenin signalling.
Highlights
Gastric cancer (GC) is currently the most common upper gastrointestinal malignancy and one of the leading causes of cancer-associated mortality worldwide[1,2]
Upregulation of MIR17HG and embedded derivatives in GC A miRNA-Seq analysis of the Cancer Genome Atlas (TCGA) database showed that 126 and 15 transcripts were upregulated and downregulated, respectively, in GC compared with adjacent gastric mucosal tissues (Fig. 1a)
interferon regulatory factor-1 (IRF-1) downregulates MIR17HG expression To explore the potential mechanisms through which miR-18a and miR-19a are regulated in GC, we investigated the transcriptional regulation of the host gene MIR17HG
Summary
Gastric cancer (GC) is currently the most common upper gastrointestinal malignancy and one of the leading causes of cancer-associated mortality worldwide[1,2]. Because the early symptoms of GC are concealed and Official journal of the Cell Death Differentiation Association. Numerous recent studies have confirmed that MIR17HG exhibits complex links to cancer metastasis. Members of the MIR17HG family are highly expressed in the invasive tumour fronts of metastatic colorectal cancer, retinoblastoma and pancreatic cancer[10,11,12]. MiR-20a enhances the invasiveness of human glioma stem cells by directly targeting the tissue inhibitor of metalloproteinases-215. These results indicate that MIR17HG has an important role in metastasis and progression and that an exploration of the inhibitory mechanism of MIR17HG will have important clinical significance for the treatment of GC
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