Increased Expression of 14-3-3β Promotes Tumor Progression and Predicts Extrahepatic Metastasis and Worse Survival in Hepatocellular Carcinoma

14-3-3 beta is implicated in cell survival, proliferation, migration, and tumor growth; however, its clinical relevance in tumor progression and metastasis have never been elucidated. To evaluate the clinical significance of 14-3-3 beta, we analyzed the association of 14-3-3 beta expression and clinicopathologic characteristics in primary and subsequent metastatic tumors of hepatocellular carcinoma patients. 14-3-3 beta was expressed abundantly in 40 of 55 (70.7%) primary tumors. Increased 14-3-3 beta expression in primary tumors predicted a higher 5-year cumulative incidence of subsequent extrahepatic metastasis, and multivariate analysis revealed 14-3-3 beta overexpression was an independent risk factor for extrahepatic metastasis. Patients with increased 14-3-3 beta expression in primary tumors had worse 5-year overall survival rates, and 14-3-3 beta overexpression was an independent prognostic factor on Cox regression analysis. Furthermore, stably overexpressed 14-3-3 beta enhanced hepatocellular carcinoma cell migration and proliferation and increased anchorage-independent cell growth. In addition, in vivo study in a nude-mice model showed tumor formation significantly increased with 14-3-3 beta overexpression. In conclusion, this is the first report to show that increased 14-3-3 beta expression is associated with subsequent extrahepatic metastasis and worse survival rates, as well as cancer progression of hepatocellular carcinoma. Thus, 14-3-3 beta may be a novel prognostic biomarker and therapeutic target in hepatocellular carcinoma. (Am J Pathol 2011, 179:2698-2708 DOI: 10.1016/j.ajpath.2011.09.010)