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MicroRNA-22 inhibits tumor growth and metastasis in gastric cancer by directly targeting MMP14 and Snail.

ABSTRACT: MicroRNAs (miRNAs) deregulation is frequent in human gastric cancers (GCs), but the role of specific miRNAs involved in this disease remains elusive. MiR-22 was previously reported to act as tumor suppressors or oncogenes in diverse cancers. However, their accurate expression, function and mechanism in GC are largely unclear. Here, we found that the expression of miR-22 was significantly reduced in clinical GC tissues compared with paired adjacent normal tissues, and was significantly correlated with a more aggressive phenotype of GC in patients, and miR-22 low expression correlated with poor overall survival. The introduction of miR-22 markedly suppressed GC cell growth, migration and invasion, and inhibition of miR-22 promoted GC cell proliferation, migration and invasion in vitro. We further demonstrated that miR-22 acted as tumor suppressors through targeting extracellular matrix (ECM) remodeling member matrix metalloproteinase 14 (MMP14) and epithelial-to-mesenchymal transition (EMT) inducer Snail in GC. Moreover, ectopic expression of MMP14 or Snail restored inhibitory effects of miR-22 on cell migration and invasion in GC cells, and a negative relationship between the miR-22 expression and MMP14 or Snail mRNA levels was observed in GC. Finally, overexpression of miR-22 suppressed tumor growth, peritoneal dissemination and pulmonary metastasis in vivo. Taken together, we identified that miR-22 is a potent tumor suppressor in GC. MiR-22 downregulation promotes GC invasion and metastasis by upregulating MMP14 and Snail, and then inducing ECM remodeling and EMT. These findings provide a better understanding of the development and progression of GC and may be an important implication for future therapy of the GC.

SUBMITTER: Zuo QF

PROVIDER: S-EPMC4670920 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:PurposeHepatocellular carcinoma (HCC), a worldwide leading cause of morbidity and mortality, is the most frequent primary liver tumor. Most HCC patients are diagnosed with advanced liver cancer, resulting in a very low 5-year survival rate. Thus, there is an urgent need for the development of targeted therapies. In this study, we aimed to investigate the effect and mechanism of the miR-20a/EZH1 axis on the proliferation and metastasis of HCC and the inhibitory effect of the EZH1/EZH2 inhibitor UNC1999 on HCC.Materials and methodsThe expression of miR-20a in human HCC tissues and cell lines was detected using quantitative real-time PCR (qRT-PCR). The expressions of proteins were analyzed with immunohistochemistry and Western blotting. Luciferase assay was used to verify whether miR-20a targets EZH1 or EZH2. The effect of miR-20a on HCC progression was studied in vivo and in vitro. The tumor inhibitory effect of UNC1999 was confirmed in vivo. CCK8 assay, wound healing assay, cell migration and invasion assay were used to evaluate the synergistic effect of UNC1999 with sorafenib. RNA sequencing (RNA-seq) was performed to screen the differentially expressed genes in the Huh7 and SMMC7721 cell lines after UNC1999, sorafenib, and combination treatments.ResultsIn this study, miR-20a showed a lower expression in both HCC tissues and cell lines. MiR-20a inhibited the proliferation and migration of SMMC7721 and Huh7 cells. The results of the luciferase assay and Western blot analysis revealed that miR-20a directly targeted EZH1, a histone methyltransferase. We demonstrated that miR-20a negatively regulated the expression of EZH1 and inhibited the proliferation and metastasis of HCC by reducing H3K27 methylation. We found UNC1999 inhibited tumor cells proliferation and enhanced the inhibitory effect of sorafenib.ConclusionWe demonstrated that miR-20a suppresses the tumor proliferation and metastasis in HCC by directly targeting EZH1. UNC1999 can inhibit tumor proliferation in vivo and increase the sensitivity of hepatoma cell lines to sorafenib.

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MicroRNA-22 inhibits tumor growth and metastasis in gastric cancer by directly targeting MMP14 and Snail.

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