Journal
INTERNATIONAL JOURNAL OF BIOCHEMISTRY & CELL BIOLOGY
Volume 59, Issue -, Pages 116-125Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.biocel.2014.11.012
Keywords
Mucin1; Transforming growth factor beta; Hepatocellular carcinoma; c-Jun N-terminal kinase; Activation protein 1
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Funding
- China National Natural Science Foundation [31170875]
- Major Development Programs for New Drugs of the Chinese Academy of Sciences during the 12th Five-Year Plan Period [2011ZX09102-001-36]
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In a previous study, we observed by global gene expression analysis that oncogene mucin1 (MUC1) silencing decreased transforming growth factor beta (TGF-beta) signaling in the human hepatocellular carcinoma (HCC) cell line SMMC-7721. In this study, we report that MUC1 overexpression enhanced the levels of phosphorylated Smad3 linker region (p-Smad3L) (Ser-213) and its target gene MMP-9 in HCC cells, suggesting that MUC1 mediates TGF-beta signaling. To investigate the effect of MUC1 on TGF-beta signaling, we determined TGF-beta secretion in MUC1 gene silencing and overexpressing cell lines. MUC1 expression enhanced not only TGF-beta 1 expression at the mRNA and protein levels but also luciferase activity driven by a TGF-beta, promoter, as well as elevated the activation of c-Jun N-terminal kinase (JNK) and c-Jun, a member of the activation protein 1 (AP-1) transcription factor family. Furthermore, pharmacological reduction of TGF-beta receptor (T beta R), JNK and c-Jun activity inhibited MUC1-induced autocrine TGF-beta signaling. Moreover, a co-immunoprecipitation assay showed that MUC1 directly bound and activated JNK. In addition, both MUC1-induced TGF-beta secretion and exogenous TGF-beta 1 significantly increased Smad signaling and cell migration, which were markedly inhibited by either T beta R inhibitor or small interfering RNA silencing of TGF-beta 1 gene in HCC cells. The high correlation between MUC1 and TGF-beta 1 or p-Smad3L (Ser-213) expression was shown in tumor tissues from HCC patients by immunohistochemical staining analysis. Collectively, these results indicate that MUC1 mediates autocrine TGF-beta signaling by activating the JNK/AP-1 pathway in HCC cells. Therefore, MUC1 plays a key role in HCC progression and could serve as an attractive target for HCC therapy. (C) 2014 Elsevier Ltd. All rights reserved.
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