Abstract
Mucin1 (MUC1), as an oncogene, plays a key role in the progression and tumorigenesis of many human adenocarcinomas. In this study, wound-healing, transwell migration and matrigel invasion assays showed that MUC1 promotes human hepatocellular carcinoma (HCC) cell migration and invasion by MUC1 gene silencing and overexpressing. Treatment with exogenous transforming growth factor beta (TGF-β)1, TGF-β type I receptor (TβRI) inhibitor, TGF-β1 siRNAs, or activator protein 1 (AP-1) inhibitor to MUC1-overexpressing HCC cells revealed that MUC1-induced autocrine TGF-β via JNK/AP-1 pathway promotes the cell migration and invasion. In addition, the migration and invasion of HCC cells were more significantly inhibited by JNK inhibitor compared with that by TβRI inhibitor or TGF-β1 siRNAs. Further studies demonstrated that MUC1-mediated JNK activation not only enhances the phosphorylation of Smad2 C-terminal at Ser-465/467 site (Smad2C) through TGF-β/TβRI, but also directly enhances the phosphorylation of Smad2 linker region at Ser-245/250/255 site (Smad2L), and then both of them collaborate to upregulate matrix metalloproteinase (MMP)-9-mediated cell migration and invasion of HCC. These results indicate that MUC1 is an attractive target in liver cancer therapy.
Highlights
Mucin1 (MUC1) is a transmembrane glycoprotein that is expressed on the apical surface of epithelial cells and is aberrantly overexpressed on most epithelial malignant tumors and some hematological malignant tumors, and it promotes the progression and tumorigenesis of many human adenocarcinomas [1,2,3,4,5]
In transwell migration and matrigel invasion assays, the results showed that the cells in the lower chamber of transwell were obviously decreased in MUC1-knockdown cells, compared with SMMC-7721 or NC (P < 0.01) (Figures 1E and 2A); in contrast, the cells in the lower chamber of transwell were significantly increased in MUC1-overexpressing cells compared with the control, respectively (P < 0.01) (Figures 1F, 1G and 2B, 2C)
The results demonstrated that MUC1 promoted the migration and invasion of hepatomacellular carcinoma (HCC) cells
Summary
Mucin (MUC1) is a transmembrane glycoprotein that is expressed on the apical surface of epithelial cells and is aberrantly overexpressed on most epithelial malignant tumors and some hematological malignant tumors, and it promotes the progression and tumorigenesis of many human adenocarcinomas [1,2,3,4,5]. Various reports and our previous studies have shown that MUC1 is overexpressed in HCC cells and tissues [21, 22]. Whether MUC1 could promote the migration and invasion of HCC cells remains unclear. We showed that MUC1 induced autocrine transforming growth factor beta (TGF-β) in HCC cells [23], leading to the hypothesis that MUC1 might activate TGF-β signaling to promote the migration and invasion of HCC cells
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