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

Abstract

14-3-3␤ 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␤, we analyzed the association of 14-3-3␤ expression and clinicopathologic characteristics in primary and subsequent metastatic tumors of hepatocellular carcinoma patients. 14-3-3␤ was expressed abundantly in 40 of 55 (70.7%) primary tumors. Increased 14-3-3␤ expression in primary tumors predicted a higher 5-year cumulative incidence of subsequent extrahepatic metastasis, and multivariate analysis revealed 14-3-3␤ overexpression was an independent risk factor for extrahepatic metastasis. Patients with increased 14-3-3␤ expression in primary tumors had worse 5-year overall survival rates, and 14-3-3␤ overexpression was an independent prognostic factor on Cox regression analysis. Furthermore, stably overexpressed 14-3-3␤ 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␤ overexpression. In conclusion, this is the first report to show that increased 14-3-3␤ expression is associated with subsequent extrahepatic metastasis and worse survival rates, as well as cancer progression of hepatocellular carcinoma. Thus, 14-3-3␤ may be a novel prognostic biomarker and therapeutic target in hepatocellular carcinoma.

A cancer-related protein 14-3-3ζ is a potential tumor-associated antigen in immunodiagnosis of hepatocellular carcinoma

“…Increased 14-3-3β expression is associated with subsequent extrahepatic metastasis and worse survival rates, as well as cancer progression of hepatocellular carcinoma [25]. The protein was found to be a candidate biomarker and a potential target for novel therapies against human HCC progression and metastasis [26].…”

Identification of 14-3-3β Gene as a Novel miR-152 Target Using a Proteome-based Approach

“…In accordance with these data, 14-3-3␤ and -have been demonstrated to be often overexpressed in human tumors of distinct origin and have been suggested as clinically relevant prognostic biomarkers due to their association with tumor progression and poor patient survival (11,48,49). This might allow the identification of tumor patients with poor prognosis to receive a more aggressive treatment.…”

“…Because many interactions of 14-3-3 members with other proteins are phosphorylation-dependent, 14-3-3␤ has been tightly integrated into the core phospho-regulatory pathways that are crucial for normal growth and development and often become deregulated in human malignancies, including cancer (45). 14-3-3␤ exerts anti-apoptotic activity, promotes tumor proliferation, and decreases overall survival of hepatocellular carcinoma patients (11). In the context of the post-transcriptional regulation of 14-3-3␤ by the tumor-suppressive miR-152, 14-3-3␤ exerts anti-apoptotic activities thereby enhancing the viability of the respective transfectants upon treatment with the chemotherapeutic drug paclitaxel due to a significant up-regulation of BCL2.…”

“…7) As miR-152 was shown to be a tumor-suppressive miR, and its expression is associated with a decreased cell proliferation and an increased apoptosis (11)(12)(13)(14), the following studies focused on the novel anti-apoptotic miR-152 target 14-3-3␤, a phosphoserine/phosphothreonine-binding protein that was down-regulated upon miR-152 expression. The highly conserved 14-3-3 protein family plays a key role in various cellular processes, such as metabolism, protein trafficking, signal transduction, apoptosis, and cell cycle regulation.…”

“…This was associated with advanced tumor staging and grading as well as reduced overall survival of tumor patients. In contrast, high miR-152 expression levels were associated with increased apoptosis, decreased cell proliferation, invasion, and angiogenesis (11)(12)(13)(14). Furthermore, plasma levels of miR-152 in tumor patients could be used as predictors of patient outcome (15).…”