Tang Yufu, Wang Ruoyu, Zhang Yibing, Lin Shenhui, Qiao Na, Sun Zhongyi, Cheng Shuqun, Zhou Wenping
Department of Hepatobiliary Surgery, The General Hospital of Shenyang Military Area Command, Shenyang, China.
Third Department of Liver Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China.
Cell Physiol Biochem. 2018;45(3):1097-1107. doi: 10.1159/000487351. Epub 2018 Feb 7.
BACKGROUND/AIMS: 14-3-3ζ is involved in the regulation of PI3K/Akt pathway which is closely associated with carcinogenesis. However, the clinical significance of combined detection of 14-3-3ζ and p-Akt in hepatocellular carcinoma (HCC) remains unclear.
Two-hundred pairs of HCC and adjacent liver specimens were subjected to tissue microarray. The association of 14-3-3ζ and p-Akt levels with the postoperative survival and recurrence in HCC patients was analyzed with univariate and multivariate methods. Moreover, the effects of 14-3-3ζ overexpression on the growth of HCC and the expressions of p-Akt and HIF-1α were assessed in a xenograft mouse model.
Elevated levels of 14-3-3ζ and p-Akt were detected in HCC and a positive correlation between the levels of 14-3-3ζ and p-Akt was verified. HCC patients with satellite nodules, microvascular invasion, portal vein tumor thrombosis, poor tumor differentiation and an advanced tumor stage tended to have higher levels of 14-3-3ζ and p-Akt. In addition, the postoperative 3-, 5-, and 7-year overall survival rates in HCC patients with 14-3-3ζhigh and p-Akthigh were significantly lower compared with those with 14-3-3ζlow and p-Aktlow, and the cumulative recurrence rate in HCC patients with 14-3-3ζhigh and p-Akthigh was significantly higher than that in those with 14-3-3ζlow and p-Aktlow. The multivariate Cox proportional hazard analysis indicated that concomitant upregulation of 14-3-3ζ and p-Akt was an independent factor that predicted poor survival and high recurrence in HCC patients. Furthermore, animal experiment showed that overexpression of 14-3-3ζ accelerated the growth of HCC xenograft tumors and induced the expressions of p-Akt and HIF-1α in vivo.
Co-upregulation of 14-3-3ζ and p-Akt predicts poor prognosis in patients with HCC, and 14-3-3ζ-induced activation of the Akt signaling pathway contributes to HCC progression.
背景/目的：14-3-3ζ参与PI3K/Akt信号通路的调控，该通路与肿瘤发生密切相关。然而，联合检测14-3-3ζ和磷酸化Akt（p-Akt）在肝细胞癌（HCC）中的临床意义仍不明确。
选取200对HCC及其癌旁肝组织标本制作组织芯片。采用单因素和多因素分析方法，分析14-3-3ζ和p-Akt水平与HCC患者术后生存及复发的相关性。此外，在异种移植小鼠模型中评估14-3-3ζ过表达对HCC生长以及p-Akt和缺氧诱导因子-1α（HIF-1α）表达的影响。
在HCC中检测到14-3-3ζ和p-Akt水平升高，且二者水平呈正相关。伴有卫星结节、微血管侵犯、门静脉癌栓、肿瘤分化差及肿瘤分期晚的HCC患者，其14-3-3ζ和p-Akt水平往往较高。此外，14-3-3ζ高表达和p-Akt高表达的HCC患者术后3年、5年和7年总生存率显著低于14-3-3ζ低表达和p-Akt低表达的患者，14-3-3ζ高表达和p-Akt高表达的HCC患者累积复发率显著高于14-3-3ζ低表达和p-Akt低表达的患者。多因素Cox比例风险分析表明，14-3-3ζ和p-Akt同时上调是预测HCC患者生存不良和高复发率的独立因素。此外，动物实验表明14-3-3ζ过表达加速了HCC异种移植瘤的生长，并在体内诱导p-Akt和HIF-1α的表达。
14-3-3ζ和p-Akt共同上调预示HCC患者预后不良，14-3-3ζ诱导的Akt信号通路激活促进HCC进展。
