The interaction between hepatitis B virus X protein and AIB1 oncogene is required for the activation of NFκB signal transduction

Hong, Andy; Han, Dong; Wright, Christine J.; Burch, Tanya C.; Piper, Jessica; Osiowy, Carla; Gao, Chunjin; Chiang, Shirley; Magill, Travis; Dick, Kevin; Booth, Timothy F.; Li, Xuguang; He, Runtao

doi:10.1016/j.bbrc.2012.05.021

Cited by 11 publications

(15 citation statements)

References 21 publications

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“…Several studies have reported on the mechanisms responsible for HBX-mediated activation of the NF-κB pathway. It is reported that HBX can enhance the activation of NF-κB pathway via interaction with several intracellular proteins including AIB1 [30], p22-FLIP [31], NEMO [31], TBK1 [32], and VCP [33]. 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].…”

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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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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“…Moreover, HBx was reported to activate NF-κB signaling through modulation of cellular signal pathways [21]–[27]; HBx activates NF-κB by inhibiting both IκB and NF-κB1 precursor, known as p105 [24], by activating Ras–Raf–MAPK pathways [26] and oxidative stress [27]. Moreover, NF-κB activation by HBx is associated with a variety of cellular proteins [28]–[32]. The association between HBx and oncogene AIB1 in the activation of NF-κB signal transduction and cell invasiveness is reported [32], [35].…”

Section: Discussionmentioning

confidence: 99%

“…Moreover, NF-κB activation by HBx is associated with a variety of cellular proteins [28]–[32]. The association between HBx and oncogene AIB1 in the activation of NF-κB signal transduction and cell invasiveness is reported [32], [35]. The chaperoning function of RPS3a is involved in HBx-mediated NF-κB activation [31].…”

Section: Discussionmentioning

confidence: 99%

“…In particular, it is well-documented that HBx activates NF-κB signaling [21]–[27]. Moreover, several studies proposed involvement of several host protein partners in this event [28]–[32]. Recently, we showed that the abnormally over-expressed RPS3a in HBV-associated HCC tissues stabilizes the HBx protein by its novel chaperoning activity and enhances HBx-induced NF-κB signaling [31].…”

Section: Introductionmentioning

confidence: 91%

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HBx-Induced NF-κB Signaling in Liver Cells Is Potentially Mediated by the Ternary Complex of HBx with p22-FLIP and NEMO

et al. 2013

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Sustained activation of NF-κB is one of the causative factors for various liver diseases, including liver inflammation and hepatocellular carcinoma (HCC). It has been known that activating the NF-κB signal by hepatitis B virus X protein (HBx) is implicated in the development of HCC. However, despite numerous studies on HBx-induced NF-κB activation, the detailed mechanisms still remain unsolved. Recently, p22-FLIP, a cleavage product of c-FLIPL, has been reported to induce NF-κB activation through interaction with the IκB kinase (IKK) complex in primary immune cells. Since our previous report on the interaction of HBx with c-FLIPL, we explored whether p22-FLIP is involved in the modulation of HBx function. First, we identified the expression of endogenous p22-FLIP in liver cells. NF-κB reporter assay and electrophoretic mobility shift assay (EMSA) revealed that the expression of p22-FLIP synergistically enhances HBx-induced NF-κB activation. Moreover, we found that HBx physically interacts with p22-FLIP and NEMO and potentially forms a ternary complex. Knock-down of c-FLIP leading to the downregulation of p22-FLIP showed that endogenous p22-FLIP is involved in HBx-induced NF-κB activation, and the formation of a ternary complex is necessary to activate NF-κB signaling. In conclusion, we showed a novel mechanism of HBx-induced NF-κB activation in which ternary complex formation is involved among HBx, p22-FLIP and NEMO. Our findings will extend the understanding of HBx-induced NF-κB activation and provide a new target for intervention in HBV-associated liver diseases and in the development of HCC.

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“…A number of host proteins have been identified as binding partners for HBx, including HBx-interacting protein (22), p53 (25), COP9 signalosome (4), apolipoprotein A1 (26), Bc-2/Bcl-x (11), nuclear receptor coactivator 3 (27), protein arginine methyltransferase 1 (28), peptidylprolyl cis/trans isomerase, NIMA-interacting 1 (29), IPS-1 (30), and S-phase kinase-associated protein 2 (31). However, the biological significance of the interaction of HBx with these host factors in the life cycle of HBV is still unclear.…”

Section: H Epatitis B Virus (Hbv) Is An Enveloped Virus Belonging To Thementioning

confidence: 99%

Hepatocyte Factor JMJD5 Regulates Hepatitis B Virus Replication through Interaction with HBx

Kouwaki

Okamoto

Ito

et al. 2016

J Virol

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The interaction between hepatitis B virus X protein and AIB1 oncogene is required for the activation of NFκB signal transduction

Cited by 11 publications

References 21 publications

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

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

HBx-Induced NF-κB Signaling in Liver Cells Is Potentially Mediated by the Ternary Complex of HBx with p22-FLIP and NEMO

Hepatocyte Factor JMJD5 Regulates Hepatitis B Virus Replication through Interaction with HBx

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