Upregulation of Focal Adhesion Kinase by 14-3-3ε via NFκB Activation in Hepatocellular Carcinoma
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
14-3-3ε 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 14-3-3ε 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 14-3-3ε 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 14-3-3ε expression was observed in
primary tumor (p<0.001) and also metastatic tumors. Furthermore, overexpression of 14-3-3ε induced FAK expression and promoter
activity which were determined by Western blotting analysis and luciferase-reporter assay. Moreover, 14-3-3ε enhanced NFκB activation
and increased nuclear translocation of NFκB. Results from chromatin immunoprecipitation assay revealed that 14-3-3ε induced NFκB
binding on FAK promoter region. These findings suggest that FAK expression is correlated with and upregulated by 14-3-3ε via
activation of NFκB. Target to suppress or inactivate FAK alone, or combine with 14-3-3ε is thus considered as the potential therapeutic
strategy for preventing HCC tumor progression.
Keywords: 14-3-3ε, Focal adhesion kinase, Hepatocellular carcinoma, Metastasis, NFκB, Survival
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