miR-451 inhibits cell proliferation in human hepatocellular carcinoma through direct suppression of IKK-β

It has been demonstrated that nuclear factor-kappa B (NF-B), which is overactivated in hepatocellular carcinoma (HCC), plays important roles in the development of HCC. Recently, a group of dysregulated micro RNAs were reported to be involved in HCC progression. Further understanding of micro RNA-mediated regulation of NF-B pathway may provide novel therapeutic targets for HCC. In this study, we found that miR-451 expression was markedly downregulated in HCC cells and tissues compared with immortalized normal liver epithelial cells and adjacent non- cancerous tissues, respectively. Upregulation of miR-451 inhibited, while downregulation of miR-451 promoted, the tumorigenicity of HCC cells both in vitro and in vivo. These changes in the properties of HCC cells were associated with deregulation of two well-known cellular G(1)/S transitional regulators, cyclin D1 and c-Myc, which are downstream targets of NF-B pathway. Furthermore, we demonstrated that miR-451 upregulation led to downregulation of cyclin D1 and c-Myc through inhibition of NF-B pathway initiated by direct targeting of the IKBKB 3-untranslated region. Therefore, these results suggest that miR-451 downregulation plays an important role in promoting proliferation of HCC cells and may provide the basis for the development of novel anti-HCC therapies.