Hepatitis B virus X protein promotes liver cell proliferation via a positive cascade loop involving arachidonic acid metabolism and p-ERK1/2

Shan, Changliang; Xu, Fu-qing; Zhang, Shuai; You, Jiacong; You, Xiaona; Qiu, Liyan; Zheng, Jie; Ye, Lihong; Zhang, Xiaodong

doi:10.1038/cr.2010.49

Cited by 66 publications

(57 citation statements)

References 56 publications

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“…HBx strongly enhances the growth of hepatoma cells in a system of stable transfection [5,12,13,32] . In the current study, we further investigated the mechanism that HBx employs to enhance the proliferation of hepatoma cells.…”

Section: Discussionmentioning

confidence: 99%

“…Previous studies have shown that HBx exhibits either apoptotic or proliferative activities in a context-dependent manner [33,34] . HBx promotes proliferation in stably transfected cells [5,12,13,32] . Therefore, we investigated the HBx-mediated proliferation in a model of stably HBx-transfected hepatoma HepG2-X cells.…”

Section: Discussionmentioning

confidence: 99%

“…Our laboratory has focused on the investigation of HBx-mediated hepatocarcinogenesis. Our findings show that arachidonic acid metabolism, extracellular signal-related kinases (ERK1/2), sterol regulatory element binding protein 1c, 5-lipoxygenase and fatty acid synthase are involved in HBx-induced cell proliferation [5,12,13] . However, the underlying mechanisms that mediate the effects of HBx on cell proliferation require further investigation.…”

Section: Introductionmentioning

confidence: 97%

“…Chronic infection is closely associated with the development of liver cirrhosis and hepatocellular carcinoma (HCC) [1,2] . The HBV X protein (HBx) is involved in the pathogenesis of HBV-associated liver diseases by affecting gene expression, apoptosis, cell cycle and cell proliferation [3][4][5] . The expression of HBx induced the transformation of human liver cells and caused the development of hepatocellular carcinoma in certain strains of transgenic mice [6,7] .…”

Section: Introductionmentioning

confidence: 99%

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Hepatitis B virus X protein promotes hepatoma cell proliferation via upregulation of MEKK2

Kong

Zhang

et al. 2011

Acta Pharmacol Sin

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Aim: To investigate the mechanism underlying the increase of hepatoma cell proliferation by hepatitis B virus X protein (HBx). Methods: HepG2, H7402 and HepG2.2.15 cells, which constitutively replicated hepatitis B virus were used. The effects of HBx on hepatoma cell proliferation were examined using 5-ethynyl-2-deoxyuridine (EdU) incorporation assay and MTT assay. The expression level of MEKK2 was measured using RT-PCR, Western blot and luciferase reporter gene assay. The activity of activator protein 1 (AP-1) was detected using luciferase reporter gene assay. The phosphorylation levels of JNK and c-Jun were measured using Western blot. The expression levels of HBx and MEKK2 in 11 clinical hepatocellular carcinoma (HCC) tissues were measured using real time PCR and Western blot. In addition, the expression of MEKK2 in 95 clinical HCC tissues was examined using immunohistochemistry. Results: HBx significantly enhanced HepG2-X cell proliferation. In HepG2-X, H7402-X and HepG2.2.15 cells, the expression level of MEKK2 was remarkably increased. In HepG2.2.15 cells, HBx was found to activate JNK and AP-1, which were the downstream effectors of MEKK2 in HepG2-X and HepG2.2.15 cells. In 11 clinical HCC tissues, both HBx and MEKK2 expression levels were remarkably increased, as compared to those in the corresponding peritumor tissues. In 95 clinical HCC tissues, the rate of detection of MEKK2 was 85.3%. Conclusion: HBx promotes hepatoma cell proliferation via upregulating MEKK2, which may be involved in hepatocarcinogenesis.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 97%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Hepatitis B virus X protein promotes hepatoma cell proliferation via upregulation of MEKK2

Kong

Zhang

et al. 2011

Acta Pharmacol Sin

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“…Our previous study showed that 5-LOX plays an important role in the activation of ERK1/2 [39] . Studies by Tong et al [25] have shown that the growth stimulatory effect of LTB4 is mediated at least through MEK/ERK pathway in human pancreatic cancer cells.…”

Section: Discussionmentioning

confidence: 99%

A novel positive feedback loop involving FASN/p-ERK1/2/5-LOX/LTB4/FASN sustains high growth of breast cancer cells

Zhao

et al. 2011

Acta Pharmacol Sin

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Aim:To investigate the endogenous signaling pathways associated with high proliferation potential of breast cancer cells. Methods: Breast cancer cell lines LM-MCF-7 and MCF-7 with high and low proliferation capability were used. The promoter activity of fatty acid synthase (FASN) was examined using luciferase reporter gene assay. The expression level of FASN mRNA was measured using RT-PCR and real time PCR, respectively. The level of leukotriene B4 (LTB4) was determined with ELISA. The expression levels of 5-lipoxygenase (5-LOX) was analyzed using RT-PCR and Western blot, respectively. 5-Bromo-20-deoxyuridine (BrdU) incorporation assay was used to study the proliferation of LM-MCF-7 and MCF-7 cells.

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JNK/c‐Jun pathway activation is essential for HBx‐induced IL‐35 elevation to promote persistent HBV infection

Zhu

et al. 2023

Clinical Laboratory Analysis

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Background Immunoregulation plays pivotal roles during chronic hepatitis B virus (HBV) infection. Studies have shown that Interleukin (IL)‐35 is an important molecule associated with inadequate immune response against HBV. However, the mechanisms involved in the up‐regulation of IL‐35 expression during persistent HBV infection remain unknown. Methods In this study, we constructed a plasmid expressing the HBV X protein (pCMV‐HBx) to evaluate the relationship between HBx and IL‐35. Activation of the JNK/c‐Jun pathway was analyzed and chromatin immunoprecipitation followed by sequencing and luciferase reporter assays were performed to determine whether c‐Jun could regulate IL‐35 transcription. Results HBx can significantly activate IL‐35 promoter in both LO2 and HepG2 cells compared to the control plasmid (pCMV‐Tag2) using the dual‐luciferase assay. Whereas other viral proteins, such as S, preS1, the core protein, had no significant effect on IL‐35 expression. Similarly, WB and qRT‐PCR also showed that HBx can significantly promote IL‐35 expression at protein and mRNA levels in the aforementioned cells. The relevant pathway mechanism showed that the expression of JNK and c‐Jun genes was significantly higher in transfected cells carrying pCMV‐HBx than in the pCMV‐Tag2‐transfected and ‐untransfected cells. WB analysis revealed that phosphorylated JNK and c‐Jun were overexpressed after HBx action. Conversely, the addition of the JNK/c‐Jun signaling pathway inhibitor could significantly suppress HBx‐induced IL‐35 expression in a dose‐dependent manner. Conclusions A novel molecular mechanism of HBV‐induced IL‐35 expression was revealed, which involves JNK/c‐Jun signaling in up‐regulating IL‐35 expression via HBx, resulting in transactivation of the IL‐35 subunit EBI3 and p35 promoter.

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Hepatitis B virus X protein promotes liver cell proliferation via a positive cascade loop involving arachidonic acid metabolism and p-ERK1/2

Cited by 66 publications

References 56 publications

Hepatitis B virus X protein promotes hepatoma cell proliferation via upregulation of MEKK2

Hepatitis B virus X protein promotes hepatoma cell proliferation via upregulation of MEKK2

A novel positive feedback loop involving FASN/p-ERK1/2/5-LOX/LTB4/FASN sustains high growth of breast cancer cells

JNK/c‐Jun pathway activation is essential for HBx‐induced IL‐35 elevation to promote persistent HBV infection

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