574444

MIR491

BACKGROUND & AIMS: Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related mortality worldwide; the prognosis of HCC patient remains poor owing to intrahepatic and extrahepatic metastasis and postsurgical recurrence. The aim of the present study is to determine the molecular mechanisms underlying the metastasis of HCC. METHODS: HCC patients and treated HCC cells were molecularly characterized by miRNA microarray analysis, qRT-PCR, Western blots, transwell assay, and immunohistochemistry. RESULTS: Here, by employing a miRNAs microarray analysis, we found that miR-491 level was the most significant down-regulation in poorly differentiated HCC tissue compared with well-differentiated HCC tissue. We then selected HepG2 (very low migratory capacity), MHCC97L (low migratory capacity) and MHCC97H (high migratory capacity), as well as HCC tissues with different status to further investigate the effects of miR-491 on the metastasis of HCC. Our data showed that miR-491 levels were inversely correlated with different status of differentiation in HCC tissues and with migratory potential in HCC cell lines. In HepG2 cells, inhibition of miR-491 increased the expression of matrix metalloproteinase 2/9 (MMP-2/9) and the migratory potential; however, in MHCC97H cells, overexpression of miR-491 level decreased the expression of MMP-2/9 and the migratory capacity. Moreover, miR-491 had a positive relationship with E-cadherin level; however, it had a negative relationship with vimentin level both in cell lines and tissue samples of HCC. MiR-491 levels of non-metastasis HCC tissue are higher than that of metastasis HCC tissue. CONCLUSION: Our results suggest that miR-491 is involved in metastasis of HCC by blocking EMT and decreasing MMP-9 levels, which may provide a new clue for preventing tumour metastasis of HCC.CI - (c) 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Hepatocellular carcinoma (HCC) is the most common liver malignancy. Current standard practices for treatment of HCC are less than satisfactory because of CSCs-mediated recurrence. For this reason, targeting CSCs, or cancer cells with CSCs-like properties, is a new approach for HCC treatment. As we reported previously, microRNA-491 (miR-491) is lower expressed in poorly differentiated HCC tissues relative to well-differentiated HCC tissues. Here, we further evaluate the effects of miR-491 on the CSCs-like properties by using HCC cell lines and HCC tissue samples. Our data showed that miR-491 had a negative relationship with CSCs-like properties both in cell lines and tissue samples of HCC. Further, miR-491 levels of non-recurrence HCC tissues were higher than those of recurrence HCC tissues. In HCC cell lines, nuclear factor kappa B (NF-kappaB)/snail pathway was involved in the epithelial to mesenchymal transition and the maintenance of CSCs-like properties. Overexpression of miR-491 targeted G-protein-coupled receptor kinase-interacting protein 1 (GIT-1), which blocked the activation of NF-kappaB by the inhibition of extracellular signal-regulated kinases (ERKs). Such process attenuated the CSCs-like properties in HCC cells. Our results point to a previously undefined mechanism by which miR-491 decreases CSCs-like properties and help to identify potential targets for the therapy of HCCs.

Gastric cancer (GC) is among the most fatal cancers in China. MicroRNAs (miRNAs) are versatile regulators during GC development and progression. miR-491-5p has been demonstrated to act as a tumor suppressor in several types of cancer. However, the role of miR-491-5p in GC metastasis remains unknown. Here, we found that miR-491-5p was significantly decreased in GC tissues compared with adjacent non-cancerous tissues, and low miR-491-5p level was associated with large tumor size. Overexpression of miR-491-5p significantly suppressed GC cell epithelial-to-mesenchymal transition (EMT) and tumor metastasis in vitro and in vivo. Mechanistically, SNAIL was identified as a direct target of miR-491-5p. The silencing of SNAIL phenocopied the tumor suppressive function of miR-491-5p, whereas re-expression of SNAIL in GC cells rescued the EMT markers and cell migratory ability that were inhibited by miR-491-5p. In addition, miR-491-5p inhibited FGFR4 indirectly. Inhibition of FGFR4 also decreased the SNAIL level and impaired EMT and cell migration. Taken together, these findings indicate that downregulation of miR-491-5p promoted GC metastasis by inducing EMT via regulation of SNAIL and FGFR4.CI - (c) 2018 The Authors. cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese cancer Association.