14-3-3β Promotes Migration and Invasion of Human Hepatocellular Carcinoma Cells by Modulating Expression of MMP2 and MMP9 through PI3K/Akt/NF-κB Pathway

14-3-3β has been demonstrated to possess the oncogenic potential, and its increased expression has been detected in multiple types of carcinomas. However, majority of previous studies focused on the role of 14-3-3β in tumor cell proliferation and apoptosis, leaving much to be elucidated about its function in tumor cell invasion and metastasis. Hence, the present study aimed to investigate the role of 14-3-3β in the invasion of hepatocellular carcinoma (HCC) cells and the implications in the prognosis of HCC patients. We first examined the expression of 14-3-3β in the primary tumors of HCC patients with or without portal vein tumor thrombus (PVTT), and found that 14-3-3β expression was higher in the primary tumors with PVTT, and the level was even higher in the PVTTs. Kaplan-Meier curves and multivariate analysis revealed that high expression of 14-3-3β was associated with overall survival (OS) and time to recurrence (TTR) of HCC patients. In addition, ectopic expression of 14-3-3β in HCC cell lines led to enhanced migration ability and invasiveness, as well as up-regulation of matrix metalloproteinase 2 and 9, which could be suppressed by inhibiting the activation of Akt and nuclear factor-κB (NF-κB) signaling. Furthermore, we identified a correlated elevation of 14-3-3β and p-Akt in the primary tumors of HCC patients, and showed that a combinatory detection of 14-3-3β and p-Akt could better predict post-surgical outcome of HCC patients.

14-3-3β蛋白已被证实具有致癌潜能，且在多种恶性肿瘤中均检测到其表达上调。然而，既往多数研究仅聚焦于14-3-3β在肿瘤细胞增殖与凋亡中的作用，其在肿瘤细胞侵袭与转移过程中的功能仍有待深入阐明。因此，本研究旨在探讨14-3-3β在肝细胞癌（hepatocellular carcinoma, HCC）细胞侵袭中的作用，及其与肝细胞癌患者预后的关联。本研究首先检测了伴或不伴门静脉癌栓（portal vein tumor thrombus, PVTT）的肝细胞癌患者原发肿瘤组织中14-3-3β的表达水平，结果发现伴PVTT的患者原发肿瘤组织中14-3-3β的表达更高，而PVTT组织中的表达水平进一步升高。Kaplan-Meier曲线及多因素分析结果显示，14-3-3β高表达与肝细胞癌患者的总生存期（overall survival, OS）及复发时间（time to recurrence, TTR）显著相关。此外，在肝细胞癌细胞系中异位表达14-3-3β可增强细胞迁移与侵袭能力，并上调基质金属蛋白酶2和9（matrix metalloproteinase 2 and 9）的表达；而抑制蛋白激酶B（Akt）及核因子κB（nuclear factor-κB, NF-κB）信号通路的激活，可逆转上述效应。进一步研究发现，肝细胞癌患者原发肿瘤组织中14-3-3β与磷酸化Akt（p-Akt）的表达水平呈正相关，且联合检测14-3-3β与p-Akt的表达可更精准地预测肝细胞癌患者的术后转归。