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MicroRNA-520e suppresses growth of hepatoma cells by targeting the NF-κB-inducing kinase (NIK)

Oncogene volume 31, pages 3607–3620 (2012)Cite this article

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Abstract

MicroRNAs (miRNAs) are small, non-coding RNAs that can act as oncogenes or tumor suppressor genes in human cancer. Emerging evidence indicates that deregulation of miRNAs contributes to the hepatocarcinogenesis. In the present study, we demonstrated that the levels of miR-520e were dramatically decreased in examined hepatoma cell lines and clinical hepatocellular carcinoma (HCC) tissues. Moreover, we found that DNA hypermethylation in the upstream region of miR-520e resulted in the downregulation of miR-520e. Next, we demonstrated that introduction of miR-520e dramatically suppressed the growth of hepatoma cells in vitro and in vivo, whereas silencing the expression of miR-520e by anti-miR-520e resulted in a promoted cell proliferation, suggesting that miR-520e may be a novel tumor suppressor. Further studies revealed that NF-κB-inducing kinase (NIK) was one of the direct target genes of miR-520e, as miR-520e directly bound to the 3′untranslated region of NIK, which reduced the expression of NIK at the levels of mRNA and protein. Moreover, silencing of NIK was able to inhibit the growth of hepatoma cells, similar to the effect of miR-520e overexpression on growth of hepatoma cells. Meanwhile, the knockdown of NIK expression reversed the enhanced proliferation mediated by anti-miR-520e. In addition, miR-520e significantly decreased the phosphorylation of ERK1/2 (p-ERK1/2) and depressed the transcriptional activity and nuclear translocation of nuclear factor κB (NF-κB) (p65). These results suggest that miR-520e suppresses the growth of hepatoma cells by targeting NIK involving the NIK/p-ERK1/2/NF-κB signaling pathway. Finally, we showed that the intratumoral injection with miR-520e was able to directly repress the growth of hepatoma cells in the nude mice. Thus, our finding provides new insight into the mechanism of hepatocarcinogenesis, indicating a therapeutic potential of miR-520e in the treatment of HCC.

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Acknowledgements

This work was supported by grants from the National Basic Research Program of China (973 Program, No. 2009CB521702) and National Natural Science Foundation of China (No. 81071624).

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Authors and Affiliations

  1. Department of Cancer Research, Key Laboratory of Molecular Microbiology and Technology of Ministry of Education, Institute For Molecular Biology, College of Life Sciences, Nankai University, Tianjin, PR China

    S Zhang, C Shan, G Kong, Y Du & X Zhang

  2. Department of Biochemistry, College of Life Sciences, Nankai University, Tianjin, PR China

    L Ye

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Zhang, S., Shan, C., Kong, G. et al. MicroRNA-520e suppresses growth of hepatoma cells by targeting the NF-κB-inducing kinase (NIK). Oncogene 31, 3607–3620 (2012). https://doi.org/10.1038/onc.2011.523

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