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Snail1-dependent transcriptional repression of Cezanne2 in hepatocellular carcinoma

Oncogene volume 33, pages 2836–2845 (2014)Cite this article

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Abstract

High malignancy and early metastasis are the hallmarks of hepatocellular carcinoma (HCC). Here, we report that Cezanne2 expression is downregulated in HCC cells and in HCC patients’ tumorous tissues and that Cezanne2 is inversely associated with Snail1 expression in HCC patients’ tumorous tissues. Chromatin immunoprecipitation assays and the reporter gene assay showed that Snail1 binds to the promoter of the Cezanne2 gene and mediates the direct consequence of Cezanne2 repression. Enhanced expression of Cezanne2 could suppress proliferation, migration and invasion in HCC cells. Further, Cezanne2 could regulate MMP (matrix metalloproteinase)2, MMP9 and ICAM1 (intercellular adhesion molecule) levels through modulation of the NF-κB (nuclear factor kappa-light-chain-enhancer of activated B cell) signaling cascade. Co-immunoprecipitation and in vivo deubiquitination assay indicated that Cezanne2 interacts with TNF receptor-associated factor (TRAF)6 and cleaves the polyubiquitin from TRAF6 substrates. Our data reveal that Snail1-mediated suppression of Cezanne2 may have a key role in HCC malignancy.

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Acknowledgements

Dr Zhongping Xu obtained his PhD in January 2011 from the Institute of Health Science, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, and at present he works as a postdoctoral fellow at the Department of Medicine, University of Chicago. Dr Zhongping Xu started to found Zhongcheng Translational-medicine Incorporation in June 2011. This study was sponsored by the Startup Package of Zhongcheng Translational-Medicine Incorporation, Shanghai, China. The nude mice were supplied by SLRC laboratory animal company, Shanghai, China.

Author contributions: ZX initiated the project, designed the experiments, analyzed the results and wrote the paper, with input from all the authors. Dr ZX, LP, YG and FZ performed most of the cellular and biochemical experiments.

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  1. Z Xu & L Pei

    Present address: 5Current Address: Department of Medicine, University of Chicago, Chicago, IL 60637, USA,

  2. Z Xu: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of molecular diagnosis, ZhongCheng Translational-Medicine Inc, Shanghai, China

    Z Xu, L Pei & F Zhang

  2. School of Medicine, Shanghai Jiaotong University, Shanghai, China

    L Wang

  3. Sir Run Run Shaw Hospital, Affiliated with School of Medicine, Zhejiang University, Hangzhou, China

    X Hu & Y Gui

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  1. Z Xu
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Correspondence to Z Xu.

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Xu, Z., Pei, L., Wang, L. et al. Snail1-dependent transcriptional repression of Cezanne2 in hepatocellular carcinoma. Oncogene 33, 2836–2845 (2014). https://doi.org/10.1038/onc.2013.243

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