HBV core promoter mutations and AKT upregulate S-phase kinase-associated protein 2 to promote postoperative hepatocellular carcinoma progression.
HBV core promoter mutations and AKT upregulate S-phase kinase-associated protein 2 to promote postoperative hepatocellular carcinoma progression.
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HBV核心启动子突变和AKT上调S期激酶相关蛋白2促进术后肝细胞癌进展
DOI：
10.1038/srep35917
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发表时间：
2016-10-25
影响因子：
4.6
通讯作者：
Huang Y
中科院分区：
文献类型：
--
作者：
Chen L;Gu L;Gu Y;Wang H;Deng M;Stamataki Z;Oo YH;Huang Y
B型肝炎病毒（HBV）核心启动子（CP）的突变已被证明与肝细胞癌（HCC）相关。CP区与HBV X基因重叠，其激活AKT以调节肝细胞存活。然而，这两个级联在HCC进展中的合作仍然知之甚少。在此，我们检测了56例肝部分切除术后肿瘤较好（BHCC，≥5年生存率）和58例肿瘤较差（PHCC，<5年生存率）的HCC患者肝组织中的病毒学因子和AKT表达。结果显示，PHCC中A1762 T/G1764 A（TA）双突变合并其他突变（TACO）和磷酸化AKT（pAKT）的发生率高于BHCC。TACO和pAKT水平与HCC样本中的增殖和微血管形成相关，但与凋亡呈负相关。当TACO和pAKT共表达时，这些更明显。由于SKP 2上调，TACO或pAKT过表达的HCC中p21和p27水平降低。在TACO表达的HCC中，E2 F1和SKP 2的mRNA和蛋白水平均升高。在pAKT过表达的HCC中，4 EBP 1/2水平降低，SKP 2 mRNA水平保持不变。因此，TACO和AKT是HCC术后生存的两个独立预测因子。它们的共同靶点SKP 2可能是诊断或治疗标志物。
Mutations in the hepatitis B virus (HBV) core promoter (CP) have been shown to be associated with hepatocellular carcinoma (HCC). The CP region overlaps HBV X gene, which activates AKT to regulate hepatocyte survival. However, the cooperation between these two cascades in HCC progression remains poorly understood. Here, we assayed virological factors and AKT expression in liver tissues from 56 HCC patients with better prognoses (BHCC, ≥5-year survival) and 58 with poor prognoses (PHCC, <5-year survival) after partial liver resection. Results showed double mutation A1762T/G1764A (TA) combined with other mutation(s) (TACO) in HBV genome and phosphorylated AKT (pAKT) were more common in PHCC than BHCC. TACO and pAKT levels correlated with proliferation and microvascularization but inversely correlated with apoptosis in HCC samples. These were more pronounced when TACO and pAKT co-expressed. Levels of p21 and p27 were decreased in TACO or pAKT overexpressing HCC due to SKP2 upregulation. Levels of E2F1 and both mRNA and protein of SKP2 were increased in TACO expressing HCC. Levels of 4EBP1/2 decreased and SKP2 mRNA level remained constant in pAKT-overexpressing HCC. Therefore, TACO and AKT are two independent predictors of postoperative survival in HCC. Their co-target, SKP2 may be a diagnostic or therapeutic marker.