Upregulation of focal adhesion kinase by 14-3-3ε via NFκB activation in hepatocellular carcinoma.

Abstract

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 14-3-3 ε 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.

• Authors: Bor-Sheng Ko, Yee-Jee Jan, Tzu-Ching Chang, Shu-Man Liang, Shyh-Chang Chen, Tzu-An Liu, Yao-Ming Wu, John Wang, Jun-Yang Liou
• Journal: Anti-cancer agents in medicinal chemistry (Anticancer Agents Med Chem) Vol. 13 Issue 4 Pg. 555-62 (May 2013) ISSN: 1875-5992 [Electronic] Netherlands
• PMID: 22934705 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• 14-3-3 Proteins
• Antineoplastic Agents
• Boronic Acids
• NF-kappa B
• Pyrazines
• Bortezomib
• Focal Adhesion Protein-Tyrosine Kinases

Topics

• 14-3-3 Proteins (antagonists & inhibitors, biosynthesis, metabolism)
• Antineoplastic Agents (pharmacology)
• Boronic Acids (pharmacology)
• Bortezomib
• Carcinoma, Hepatocellular (diagnosis, drug therapy, metabolism)
• Cell Survival (drug effects)
• Drug Screening Assays, Antitumor
• Female
• Focal Adhesion Protein-Tyrosine Kinases (antagonists & inhibitors, biosynthesis, metabolism)
• Humans
• Kaplan-Meier Estimate
• Liver Neoplasms (diagnosis, drug therapy, metabolism)
• Male
• Middle Aged
• NF-kappa B (antagonists & inhibitors, metabolism)
• Pyrazines (pharmacology)
• Structure-Activity Relationship
• Tumor Cells, Cultured
• Up-Regulation (drug effects)