Hepatic Surgery Centre, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology; Hubei Province for the Clinical Medicine Research Center of Hepatic Surgery; Key Laboratory of Organ Transplantation, Ministry of Education and Ministry of Public Health, Wuhan, Hubei 430030, P.R. China.
Int J Oncol. 2017 Nov;51(5):1449-1459. doi: 10.3892/ijo.2017.4126. Epub 2017 Sep 15.
Hepatitis B virus (HBV) is the dominant risk factor for hepatocellular carcinoma (HCC). HBV X protein (HBx) plays crucial roles in HCC carcinogenesis. HBx interferes with several signaling pathways including the Notch1 pathway in HCC. In this study, we found that Notch1 was highly expressed in HCC, especially in large HCCs. Notch1 and HBx co-localized in HCC and their levels were positively correlated with each other. Notch1 expression was more elevated in HepG2.2.15 cells than that in HepG2 cells. HBx activated the Notch1 pathway in HepG2.2.15 cells. Suppression of HBx and the Notch1 pathway attenuated the growth of HepG2.2.15 cells. Notch1, ERK, and AKT pathways were inhibited after γ-secretase inhibitor treatment. Dual-specificity phosphatase 1 (DUSP1) and phosphatase and tensin homolog (PTEN) were upregulated after γ-secretase inhibitor treatment and Hes1 inhibition. Luciferase reporter assays showed that Hes1 suppressed the promoters of DUSP1 and PTEN genes, which was reversed by γ-secretase inhibitor treatment. Western blotting demonstrated that DUSP1 dephosphorylated pERK and PTEN dephosphorylated pAKT. Collectively, we found a link among HBx, the Notch1 pathway, DUSP1/PTEN, and ERK/AKT pathways, which influenced HCC cell survival and could be a therapeutic target for HCC treatment.
乙型肝炎病毒 (HBV) 是肝细胞癌 (HCC) 的主要危险因素。HBV X 蛋白 (HBx) 在 HCC 的发生中起着至关重要的作用。HBx 干扰了几种信号通路，包括 HCC 中的 Notch1 通路。在这项研究中，我们发现 Notch1 在 HCC 中高度表达，尤其是在大 HCC 中。Notch1 和 HBx 在 HCC 中共定位，它们的水平相互正相关。与 HepG2 细胞相比，HBx 在 HepG2.2.15 细胞中的表达水平更高。HBx 在 HepG2.2.15 细胞中激活 Notch1 通路。抑制 HBx 和 Notch1 通路可减弱 HepG2.2.15 细胞的生长。γ-分泌酶抑制剂处理后，Notch1、ERK 和 AKT 通路被抑制。γ-分泌酶抑制剂处理和 Hes1 抑制后，双特异性磷酸酶 1 (DUSP1) 和磷酸酶和张力蛋白同源物 (PTEN) 上调。荧光素酶报告基因检测表明 Hes1 抑制了 DUSP1 和 PTEN 基因的启动子，而 γ-分泌酶抑制剂处理可逆转这一现象。Western blot 实验表明 DUSP1 去磷酸化 pERK，PTEN 去磷酸化 pAKT。总之，我们发现了 HBx、Notch1 通路、DUSP1/PTEN 和 ERK/AKT 通路之间的联系，这些通路影响 HCC 细胞的存活，可能成为 HCC 治疗的一个靶点。
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