Journal
ONCOGENE
Volume 33, Issue 22, Pages 2836-2845Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/onc.2013.243
Keywords
Snail1; Cezanne2; HCC; metastasis
Funding
- Institute of Health Science, Shanghai Institutes for Biological Sciences
- Chinese Academy of Sciences
- Department of Medicine, University of Chicago
- Startup Package of Zhongcheng Translational- Medicine Incorporation, Shanghai, China
- SLRC laboratory animal company, Shanghai, China
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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-kappa B (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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