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MicroRNA-26b inhibits tumor metastasis by targeting the KPNA2/c-jun pathway in human gastric cancer.

ABSTRACT: MicroRNAs (miRNA) play an important role in carcinogenesis. Previously, we identified miR-26b as a significantly downregulated miRNA in gastric cancer (GC) tissues (n = 106) based on differential quantitative RT-PCR (RT-qPCR) miRNA expression profiles. In the current study, we aimed to clarify the potential role of miR-26b and related target genes in GC progression. Downregulation of miR-26b was associated with advanced tumor-node-metastasis stage (TNM stage) and poor 5-year survival rate. Forced expression of miR-26b led to inhibition of GC cell migration and invasion in vitro and lung metastasis formation in vivo. Conversely, depletion of miR-26b had stimulatory effects. Additionally, miR-26b affected GC cell behavior through negative regulation of the metastasis promoter, karyopherin alpha 2 (KPNA2). Ectopic expression of miR-26b induced a reduction in KPNA2 protein levels, confirmed by luciferase assay data showing that miR-26b directly binds to the 3' untranslated regions (UTR) of KPNA2 mRNA. Furthermore, miR-26b and KPNA2 mRNA/protein expression patterns were inversely correlated in GC tissues. Cag A of Helicobacter pylori (Hp) enhanced miR-26b levels through regulation of the KPNA2/c-jun pathway. Taken together, our data indicate that miR-26b plays an anti-metastatic role and is downregulated in GC tissues via the KPNA2/c-jun pathway. Based on the study findings, we propose that miR-26b overexpression or KPNA2/c-jun suppression may have therapeutic potential in inhibiting GC metastasis.

SUBMITTER: Tsai MM

PROVIDER: S-EPMC5129949 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Metastasis is responsible for the rapid recurrence and poor survival of malignancies. Epithelial-mesenchymal transition (EMT) has a critical role in metastasis. Increasing evidence indicates that EMT can be regulated by microRNAs (miRNAs). The aim of this study was to investigate the role of miR-26b in modulating epithelial-mesenchymal transition (EMT) in hepatocellular carcinoma (HCC), as well as to identify its underlying mechanism of action.The expression level of miR-26b was assessed in multiple HCC cell lines (HepG2, MHCC97H, Hep3B, MHCC97L, HCCC9810, BEL-7402, Huh7 and QGY-7703), as well as in liver tissue from patients with HCC. Follow-up studies examined the effects of a miR-26b mimic (increased expression) and a miR-26b inhibitor (decreased expression) on markers of EMT, wound healing and cell migration. The molecular target of miR-26b was also identified using a computer algorithm and confirmed experimentally.MiR-26b expression was decreased in HCC cell lines and was inversely correlated with the grade of HCC. Increased expression of miR-26b inhibited the migration and invasiveness of HCC cell lines, which was accompanied by decreased expression of the epithelial marker E-cadherin and increased expression of the mesenchymal marker vimentin, at both the mRNA and protein expression levels. A binding site for miR-26b was theoretically identified in the 3'UTR of USP9X. Further studies revealed that overexpression of miR-26b repressed the endogenous level of USP9X protein expression. Overexpression of miR-26b also repressed Smad4 expression, whereas its inhibition elevated Smad4 expression.Taken together, our results indicate that miR-26b were inhibited in HCC. In HCC cell lines, miR-26b targeted the 3'UTR of USP9X, which in turn affects EMT through Smad4 and the TGF-? signaling pathway. Our analysis of clinical HCC samples verifies that miR-26b also targets USP9X expression to inhibit the EMT of hepatocytes. Thus, miR-26b may have some effects on the EMT of HCC cells.

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MicroRNA-26b inhibits tumor metastasis by targeting the KPNA2/c-jun pathway in human gastric cancer.

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