Department of Interventional Radiology, the First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong 510080, China.
Carcinogenesis. 2013 Nov;34(11):2443-51. doi: 10.1093/carcin/bgt206. Epub 2013 Jun 5.
It has been demonstrated that nuclear factor-kappa B (NF-κB), 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-κB 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 G1/S transitional regulators, cyclin D1 and c-Myc, which are downstream targets of NF-κB pathway. Furthermore, we demonstrated that miR-451 upregulation led to downregulation of cyclin D1 and c-Myc through inhibition of NF-κB 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.
已经证实，核因子-κB（NF-κB）在肝癌（HCC）中过度激活，在 HCC 的发展中发挥重要作用。最近，有一组失调的 microRNA 被报道参与 HCC 的进展。进一步了解 microRNA 介导的 NF-κB 通路的调控可能为 HCC 提供新的治疗靶点。在本研究中，我们发现与永生化正常肝上皮细胞和相邻非癌组织相比，miR-451 在 HCC 细胞和组织中的表达明显下调。miR-451 的上调抑制了 HCC 细胞的体外和体内致瘤性，而 miR-451 的下调则促进了 HCC 细胞的致瘤性。这些 HCC 细胞特性的变化与 NF-κB 通路下游的两个众所周知的细胞 G1/S 过渡调节因子 cyclin D1 和 c-Myc 的失调有关。此外，我们还证明，miR-451 的上调通过直接靶向 IKBKB 3'非翻译区抑制 NF-κB 通路，导致 cyclin D1 和 c-Myc 的下调。因此，这些结果表明 miR-451 的下调在促进 HCC 细胞增殖中起着重要作用，并为开发新型抗 HCC 治疗方法提供了依据。
