期刊
ONCOTARGET
卷 6, 期 22, 页码 19264-19278出版社
IMPACT JOURNALS LLC
DOI: 10.18632/oncotarget.4267
关键词
Mucin1; HCC; JNK; TGF-beta; Smad2L/C
资金
- Double Tenth Engineering of Major Research Project of Jilin Provincial Science and Technology Department [20140201012YY]
- Major Development Programs for New Drugs of the Chinese Academy of Sciences during the 12th Five-Year Plan Period [2011ZX09102-001-36]
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-beta) 1, TGF-beta type I receptor (T beta RI) inhibitor, TGF-beta 1 siRNAs, or activator protein 1 (AP-1) inhibitor to MUC1-overexpressing HCC cells revealed that MUC1-induced autocrine TGF-beta 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 T beta RI inhibitor or TGF-beta 1 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-beta/T beta RI, 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.
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