Focal adhesion kinase (FAK) is implicated in cancer cell survival, proliferation and migration. Expression of FAK expression is elevated and associated with tumor progression and metastasis in various tumors, including hepatocellular carcinoma (HCC). Increased 14-3-3epsilon expression is shown to be a potential prognostic factor to predict higher risk of distant metastasis and worse overall survival in HCC. The aim of this study is to investigate whether FAK is associated or regulated by 14-3-3epsilon to modulate tumor progression in HCC. In this study, 114 primary HCC tumors including 34 matched metastatic tumors were subjected to immunohistochemistry analysis of FAK and 14-3-3epsilon expression. Overexpression of FAK was significantly associated with increased risk of extrahepatic metastasis (p=0.027) and reduced 5-year overall survival rate (p=0.017). A significant correlation of FAK and 14-3-3epsilon expression was observed in primary tumor (p<0.001) and also metastatic tumors. Furthermore, overexpression of 14-3-3epsilon induced FAK expression and promoter activity which were determined by Western blotting analysis and luciferase-reporter assay. Moreover, 14-3-3epsilon enhanced NFkappaB activation and increased nuclear translocation of NFkappaB. Results from chromatin immunoprecipitation assay revealed that 14-3-3epsilon induced NFkappaB binding on FAK promoter region. These findings suggest that FAK expression is correlated with and upregulated by 14-3-3epsilon via activation of NFkappaB. Target to suppress or inactivate FAK alone, or combine with 14-3-3epsilon is thus considered as the potential therapeutic strategy for preventing HCC tumor progression.
Date:
2013-05
Relation:
Anti-Cancer Agents in Medicinal Chemistry. 2013 May;13(4):555-562 .
