Hepatitis B virus X protein activates Notch signaling by its effects on Notch1 and Notch4 in human hepatocellular carcinoma

Gao, Juan; Xiong, Yimin; Wang, Yan; Wang, Yiming; Guo, Zheng; Xu, Hualin

doi:10.3892/ijo.2015.3221

Cited by 33 publications

(27 citation statements)

References 41 publications

(41 reference statements)

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“…Notch1 is overexpressed in HCC (14). Consistent with the results of previous studies, we found that Notch1 expression in tumor tissues was much more elevated than that in peritumoral, cirrhosis, and normal tissues by IHC and western blot analyses.…”

Section: Discussionsupporting

confidence: 80%

“…Consistent with the results of previous studies, we found that Notch1 expression in tumor tissues was much more elevated than that in peritumoral, cirrhosis, and normal tissues by IHC and western blot analyses. Previous reports have shown co-localization of Notch1 with HBx (14). In our study, we found that inhibition of the Notch1 pathway downregulated the phosphorylated levels of ERK and AKT.…”

Section: Discussionsupporting

confidence: 64%

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Regulation of ERK and AKT Pathways by Hepatitis B Virus X Protein via Notch1 Pathway in Hepatocellular Carcinoma

Liao

Zhou

Liang

et al. 2016

Preprint

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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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Section: Discussionsupporting

confidence: 80%

Section: Discussionsupporting

confidence: 64%

Regulation of ERK and AKT Pathways by Hepatitis B Virus X Protein via Notch1 Pathway in Hepatocellular Carcinoma

Liao

Zhou

Liang

et al. 2016

Preprint

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“…Taken together, these results indicate that activation of NF-κB and Notch1 pathways is responsible for IL-7R in cells with different types. Numerous studies have indicated that HBX can stimulate NF-κB and Notch1 pathways to alter the expression of different genes and thereby promote the development of HCC [11, 27–29]. Several studies have reported on the mechanisms responsible for HBX-mediated activation of the NF-κB pathway.…”

Section: Discussionmentioning

confidence: 99%

“…Besides, HBX has been demonstrated to activate NF-κB signaling pathway dependently on other signaling pathways such as PI3-K and Notch 1 [34–36]. With respect to the HBX-induced activation of Notch1, Gao J et al has shown that HBX upregulated the expression of Notch1 is mainly dependent on p38 MAPK pathway in HCC cells [29]. Additionally, Kongkavitoon P et al suggested that NF-κB, PI3-K, and MEK1/2 signaling pathways contribute to the activation of Notch1 [28].…”

Section: Discussionmentioning

confidence: 99%

Hepatitis B virus X protein promotes interleukin-7 receptor expression via NF-κB and Notch1 pathway to facilitate proliferation and migration of hepatitis B virus-related hepatoma cells

Kong

Zhou

et al. 2016

J Exp Clin Cancer Res

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BackgroundInterleukin-7 receptor (IL-7R) is involved in the abnormal function of solid tumors, but the role and regulatory mechanisms of IL-7R in HBV-related hepatocellular carcinoma (HCC) are still unclear.MethodsGene and protein expression levels of IL-7R were examined in hepatoma cells transfected with hepatitis B virus (HBV) plasmids and in hepatoma cells transfected with the multifunctional nonstructural protein X (HBX). The expression of HBX and IL-7R was measured by immunohistochemical analysis in HBV-related HCC tissues. The role of NF-κB and Notch1 pathways in HBX-mediated expression of IL-7R in hepatoma cells was examined. Activation of IL-7R downstream of intracellular signaling proteins AKT, JNK, STAT5, and the associated molecules CyclinD1 and matrix metalloproteinase-9 (MMP)-9, was assessed in HBX-positive cells with or without treatment with IL-7R short hairpin RNA (shRNA). Additionally, the role of IL-7R in HBX-mediated proliferation and migration of hepatoma cells was investigated.ResultsThe expression of IL-7R was increased in hepatoma cells transfected with HBV plasmids; HBX was responsible for the HBV-mediated upregulation of IL-7R. Compared to adjacent tissues, the expression of HBX and IL-7R was increased in HBV-related HCC tissues. Additionally, the relative expression levels of HBX were associated with IL-7R in HBV-related HCC tissues. The activation of NF-κB pathways and expression of Notch1 were increased in hepatoma cells transfected with HBX, and inhibition of NF-κB and Notch1 pathways significantly decreased HBX-mediated expression of IL-7R. The activation of AKT and JNK and the expression of CyclinD1 and MMP-9 were increased in HBX-positive cells. When cells were treated with IL-7R shRNA, the activation of AKT and JNK, as well as the expression of CyclinD1 and MMP-9, were significantly inhibited. Additionally, IL-7R was responsible for HBX-induced proliferation and migration ability of hepatoma cells.ConclusionsOur data demonstrate that HBX can upregulate IL-7R via NF-κB and Notch1 pathways to facilitate the activation of intracellular pathways and expression of associated molecules, and contribute to proliferation and migration of hepatoma cells.

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“…HCC occurs usually in the background of chronic liver diseases, such as hepatitis virus infection and liver cirrhosis [2, 3]. The prevalence of hepatitis B virus (HBV) carriage is reported to be 350 million people worldwide [4].…”

Section: Introductionmentioning

confidence: 99%

TFCP2 Genetic Polymorphism Is Associated with Predisposition to and Transplant Prognosis of Hepatocellular Carcinoma

Liu

Gao

Shao

et al. 2017

Gastroenterology Research and Practice

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TFCP2 is an oncogene and plays crucial roles in the incidence and progression of hepatocellular carcinoma (HCC). However, no reports are available on the impact of TFCP2 genetic polymorphism on the susceptibility to and the transplant prognosis of HCC. Here, we genotyped 7 SNPs of TFCP2 in a case-control study of 119 patients with HCC and 200 patients with chronic liver disease. Of the 7 SNPs in TFCP2, rs7959378 distributed differentially between patients with versus patients without HCC. The patients with the CA (OR = 0.58, 95% CI = 0.35–0.96), the CC (OR = 0.39, 95% CI = 0.20–0.76), and the CA/CC (OR = 0.52, 95% CI = 0.32–0.83) genotypes had significantly decreased risk for HCC compared with those carrying the rs7959378 AA genotype. After adjusting for confounding factors, rs7959378 still conferred significant risk for HCC. Furthermore, the patients who carried rs7959378 AC/CC had a higher overall survival and lower relapse-free survival than those with the rs7959378 AA genotype. Similar results were found in the multivariate analysis adjusted by AFP, tumor size and tumor number, and differentiation. These findings indicate that rs7959378 is associated with the risk of HCC in patient with chronic liver disease and prognosis of HCC patients after liver transplantation.

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Hepatitis B virus X protein activates Notch signaling by its effects on Notch1 and Notch4 in human hepatocellular carcinoma

Cited by 33 publications

References 41 publications

Regulation of ERK and AKT Pathways by Hepatitis B Virus X Protein via Notch1 Pathway in Hepatocellular Carcinoma

Regulation of ERK and AKT Pathways by Hepatitis B Virus X Protein via Notch1 Pathway in Hepatocellular Carcinoma

Hepatitis B virus X protein promotes interleukin-7 receptor expression via NF-κB and Notch1 pathway to facilitate proliferation and migration of hepatitis B virus-related hepatoma cells

TFCP2 Genetic Polymorphism Is Associated with Predisposition to and Transplant Prognosis of Hepatocellular Carcinoma

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