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

• Published in: Carcinogenesis (New York) 2013-11, Vol.34 (11), p.2443-2451
• Main Authors: Li, He-Ping, Zeng, Xian-Cheng, Zhang, Bing, Long, Jian-Ting, Zhou, Bo, Tan, Guo-Sheng, Zeng, Wei-Xia, Chen, Wei, Yang, Jian-Yong
• Format: Article
• Language: English
• Subjects: Animals; Apoptosis; Blotting, Western; Carcinoma, Hepatocellular - genetics; Carcinoma, Hepatocellular - metabolism; Carcinoma, Hepatocellular - pathology; Cell Adhesion; Cell Cycle; Cell Movement; Cell Proliferation; Cyclin D1 - genetics; Cyclin D1 - metabolism; Flow Cytometry; Fluorescent Antibody Technique; Gene Expression Regulation, Neoplastic; Humans; I-kappa B Kinase - antagonists & inhibitors; I-kappa B Kinase - genetics; I-kappa B Kinase - metabolism; Liver Neoplasms - genetics; Liver Neoplasms - metabolism; Liver Neoplasms - pathology; Mice; Mice, Inbred BALB C; Mice, Nude; MicroRNAs - genetics; NF-kappa B - genetics; NF-kappa B - metabolism; Proto-Oncogene Proteins c-myc - genetics; Proto-Oncogene Proteins c-myc - metabolism; Real-Time Polymerase Chain Reaction; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger - genetics; RNA, Small Interfering - genetics; Tumor Cells, Cultured
• ISSN: 0143-3334; 1460-2180
• DOI: 10.1093/carcin/bgt206

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.