Regulation of ERK and AKT pathways by hepatitis B virus X protein via the Notch1 pathway in hepatocellular carcinoma

Liao,Bo; Zhou,Honghao; Liang,Huifang; Li,Changhai

doi:10.3892/ijo.2017.4126

Regulation of ERK and AKT pathways by hepatitis B virus X protein via the Notch1 pathway in hepatocellular carcinoma

Authors:
- Bo Liao
- Honghao Zhou
- Huifang Liang
- Changhai Li
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Affiliations: 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
Published online on: September 15, 2017 https://doi.org/10.3892/ijo.2017.4126
Pages: 1449-1459
Copyright: © Liao et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

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.

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