title: Mucin1 mediates autocrine transforming growth factor beta signaling through activating the c-Jun N-terminal kinase/activator protein 1 pathway in human hepatocellular carcinoma cells.
abstract: In a previous study, we observed by global gene expression analysis that oncogene mucin1 (MUC1) silencing decreased transforming growth factor beta (TGF-β) 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-β signaling. To investigate the effect of MUC1 on TGF-β signaling, we determined TGF-β secretion in MUC1 gene silencing and overexpressing cell lines. MUC1 expression enhanced not only TGF-β1 expression at the mRNA and protein levels but also luciferase activity driven by a TGF-β 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-β receptor (TβR), JNK and c-Jun activity inhibited MUC1-induced autocrine TGF-β signaling. Moreover, a co-immunoprecipitation assay showed that MUC1 directly bound and activated JNK. In addition, both MUC1-induced TGF-β secretion and exogenous TGF-β1 significantly increased Smad signaling and cell migration, which were markedly inhibited by either TβR inhibitor or small interfering RNA silencing of TGF-β1 gene in HCC cells. The high correlation between MUC1 and TGF-β1 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-β 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.
authors.affiliation: Department of Immunology, College of Basic Medical Science, Jilin University, Changchun 130021, China.
authors.forename: Qiongshu
authors.initials: Q
authors.lastname: Li
authors.affiliation: Department of Immunology, College of Basic Medical Science, Jilin University, Changchun 130021, China.
authors.forename: Guomu
authors.initials: G
authors.lastname: Liu
authors.affiliation: Department of Immunology, College of Basic Medical Science, Jilin University, Changchun 130021, China.
authors.forename: Dan
authors.initials: D
authors.lastname: Shao
authors.affiliation: Department of Immunology, College of Basic Medical Science, Jilin University, Changchun 130021, China.
authors.forename: Juan
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Immunology, College of Basic Medical Science, Jilin University, Changchun 130021, China.
authors.forename: Hongyan
authors.initials: H
authors.lastname: Yuan
authors.affiliation: Department of Immunology, College of Basic Medical Science, Jilin University, Changchun 130021, China.
authors.forename: Tanxiu
authors.initials: T
authors.lastname: Chen
authors.affiliation: Department of Immunology, College of Basic Medical Science, Jilin University, Changchun 130021, China.
authors.forename: Ruiping
authors.initials: R
authors.lastname: Zhai
authors.affiliation: Department of Immunology, College of Basic Medical Science, Jilin University, Changchun 130021, China.
authors.forename: Weihua
authors.initials: W
authors.lastname: Ni
authors.affiliation: Department of Immunology, College of Basic Medical Science, Jilin University, Changchun 130021, China. Electronic address: taiguixiang@163.com.
authors.forename: Guixiang
authors.initials: G
authors.lastname: Tai
mesh_terms: D019898:Autocrine Communication; D006528:Carcinoma, Hepatocellular / Q000201:enzymology* / Q000473:pathology; D045744:Cell Line, Tumor; D002465:Cell Movement; D004789:Enzyme Activation; D055785:Gene Knockdown Techniques; D020868:Gene Silencing; D057809:HEK293 Cells; D006801:Humans; D008113:Liver Neoplasms / Q000201:enzymology* / Q000473:pathology; D048055:Mitogen-Activated Protein Kinase 8 / Q000378:metabolism*; D018396:Mucin-1 / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D011485:Protein Binding; D051900:Smad3 Protein / Q000378:metabolism; D018808:Transcription Factor AP-1 / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000378:metabolism*
chemical_list: D018396:Mucin-1; D051900:Smad3 Protein; D018808:Transcription Factor AP-1; D016212:Transforming Growth Factor beta; D048055:Mitogen-Activated Protein Kinase 8
keywords: Activation protein 1; Hepatocellular carcinoma; Mucin1; Transforming growth factor beta; c-Jun N-terminal kinase