452 IN VIVO INHIBITORY EFFECTS OF HEPATITIS B VIRUS X PROTEIN ON LIVER REGENERATION THROUGH A IL-6 DEPENDENT MECHANISM

ABSTRACT Chronic infection with hepatitis B virus (HBV) is one of the major etiological factors in the development of human hepatocellular carcinoma. Transgenic mice that express the HBV X protein (HBx) have previously been shown to be more sensitive to the effects of hepatocarcinogens, although the mechanism for this cofactor role remains unknown. The ability of HBx to inhibit DNA repair in transiently transfected cell lines suggests one possible pathway. In the present study, primary hepatocytes isolated from transgenic mice that possess the HBV X gene under the control of the human α-1-antitrypsin regulatory region (ATX mice) were found to be deficient in their ability to conduct unscheduled DNA synthesis in response to UV-induced DNA damage. In order to measure the impact of HBx expression on DNA repair in vivo, double-transgenic mice that express HBx and possess a bacteriophage lambda transgene were sacrificed at 30, 90, and 240 days of age. Mutation frequency was determined for high-molecular-weight liver DNA of ATX and control mice by functional analysis of the lambda transgene. Expression of HBx did not significantly increase the accumulation of spontaneous mutations. These results are consistent with previous studies of HBx transgenic mice in which no effect of HBx on liver histology was apparent. This new animal model provides a powerful system in which to investigate the in vivo cooperation between HBx expression and environmental carcinogens.

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630 HEPATITIS B VIRUS X PROTEIN AUGMENTS HBV TRANSCRIPTION AND REPLICATION IN VIVO OF MOUSE

Journal of Hepatology ◽

10.1016/s0168-8278(10)60632-0 ◽

2010 ◽

Vol 52 ◽

pp. S247

Author(s):

F.-J. Huang ◽

H. Tang ◽

Q.-L. Hou ◽

E.-Q. Chen ◽

F.-J. Liu ◽

...

Keyword(s):

Hepatitis B Virus ◽

Hepatitis B ◽

X Protein ◽

B Virus ◽

Transcription And Replication

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Anti-oncogene PTPN13 inactivation by hepatitis B virus X protein counteracts IGF2BP1 to promote hepatocellular carcinoma progression

Oncogene ◽

10.1038/s41388-020-01498-3 ◽

2020 ◽

Vol 40 (1) ◽

pp. 28-45 ◽

Cited By ~ 1

Author(s):

Yongcong Yan ◽

Pinbo Huang ◽

Kai Mao ◽

Chuanchao He ◽

Qiaodong Xu ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Hepatitis B Virus ◽

Hepatitis B ◽

Tyrosine Phosphatase ◽

Cellular Protein ◽

Metabolic Reprogramming ◽

X Protein ◽

B Virus

AbstractHepatitis B x protein (HBx) affects cellular protein expression and participates in the tumorigenesis and progression of hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC). Metabolic reprogramming contributed to the HCC development, but its role in HBV-related HCC remains largely unclear. Tyrosine-protein phosphatase nonreceptor type 13 (PTPN13) is a significant regulator in tumor development, however, its specific role in hepatocarcinogenesis remains to be explored. Here, we found that decreased PTPN13 expression was associated with HBV/HBx. Patients with low PTPN13 expression showed a poor prognosis. Functional assays revealed that PTPN13 inhibited proliferation and tumorigenesis in vitro and in vivo. Further mechanistic studies indicated that HBx inhibited PTPN13 expression by upregulating the expression of DNMT3A and interacting with DNMT3A. Furthermore, we found that DNMT3A bound to the PTPN13 promoter (−343 to −313 bp) in an epigenetically controlled manner associated with elevated DNA methylation and then inhibited PTPN13 transcription. In addition, we identified IGF2BP1 as a novel PTPN13-interacting gene and demonstrated that PTPN13 influences c-Myc expression by directly and competitively binding to IGF2BP1 to decrease the intracellular concentration of functional IGF2BP1. Overexpressing PTPN13 promoted c-Myc mRNA degradation independent of the protein tyrosine phosphatase (PTP) activity of PTPN13. Importantly, we discovered that the PTPN13-IGF2BP1-c-Myc axis was important for cancer cell growth through promoting metabolic reprogramming. We verified the significant negative correlations between PTPN13 expression and c-Myc, PSPH, and SLC7A1 expression in clinical HCC tissue samples. In summary, our findings demonstrate that PTPN13 is a novel regulator of HBV-related hepatocarcinogenesis and may play an important role in HCC. PTPN13 may serve as a prognostic marker and therapeutic target in HBV-related HCC patients.

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Altered DNA Mutation Spectrum in Aflatoxin B1-Treated Transgenic Mice That Express the Hepatitis B Virus X Protein

Journal of Virology ◽

10.1128/jvi.76.22.11770-11774.2002 ◽

2002 ◽

Vol 76 (22) ◽

pp. 11770-11774 ◽

Cited By ~ 27

Author(s):

Charles R. Madden ◽

Milton J. Finegold ◽

Betty L. Slagle

Keyword(s):

Hepatitis B Virus ◽

Hepatitis B ◽

Transgenic Mice ◽

Aflatoxin B1 ◽

Environmental Carcinogens ◽

X Protein ◽

Dna Mutation ◽

Dna Mutations ◽

B Virus

ABSTRACT Humans chronically infected with hepatitis B virus (HBV) are at further risk of liver cancer upon exposure to dietary aflatoxin B1 (AFB1), a carcinogenic product of the mold Aspergillus flavus. For the present study, we utilized double-transgenic mice (ATX mice) that express the HBV X protein (HBx) and possess a bacteriophage lambda transgene to evaluate the in vivo effect of HBx expression on AFB1-induced DNA mutations. The expression of HBx correlated with a 24% increase in mutation frequency overall and an approximately twofold increase in the incidence of G/C-to-T/A transversion mutations following AFB1 exposure. These results are consistent with a model in which expression of HBx during chronic HBV infection may contribute to the development of hepatocellular carcinoma following exposure to environmental carcinogens.

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Inhibitory effects of resveratrol on hepatitis B virus X protein-induced hepatocellular carcinoma

Journal of Veterinary Science ◽

10.4142/jvs.2017.18.4.419 ◽

2017 ◽

Vol 18 (4) ◽

pp. 419 ◽

Cited By ~ 4

Author(s):

Seungmo Park ◽

Jihae Lim ◽

Jong Rhan Kim ◽

Seongbeom Cho

Keyword(s):

Hepatocellular Carcinoma ◽

Hepatitis B Virus ◽

Hepatitis B ◽

Inhibitory Effects ◽

X Protein ◽

B Virus

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Sustained Activation of Mitogen-Activated Protein Kinases and Activator Protein 1 by the Hepatitis B Virus X Protein in Mouse Hepatocytes In Vivo

Journal of Virology ◽

10.1128/jvi.75.21.10348-10358.2001 ◽

2001 ◽

Vol 75 (21) ◽

pp. 10348-10358 ◽

Cited By ~ 61

Author(s):

Ruchika Nijhara ◽

Siddhartha S. Jana ◽

Shyamal K. Goswami ◽

Ajay Rana ◽

Subeer S. Majumdar ◽

...

Keyword(s):

Hepatitis B Virus ◽

Hepatitis B ◽

Dependent Manner ◽

Activator Protein 1 ◽

X Protein ◽

Activator Protein ◽

B Virus ◽

Mitogen Activated Protein ◽

Sustained Activation

ABSTRACT Transcriptional activation of diverse cellular genes by the X protein (HBx) of hepatitis B virus (HBV) has been suggested as one of the mechanisms for HBV-associated hepatocellular carcinoma. However, such functions of HBx have been studied using transformed cells in culture and have not been examined in the normal adult hepatocytes, a natural host of HBV. Using an efficient hepatocyte-specific virus-based gene delivery system developed in our laboratory earlier, we studied the HBx action in vivo. We demonstrate that following virosome-mediated delivery of HBx DNA, a large population (>50%) of hepatocytes express the HBx protein in a dose-dependent manner, which induces a significant increase in the activity of extracellular signal-regulated kinases (ERKs) in the livers of HBx-transfected mice. Inhibition of HBx-induced ERK activation following intravenous administration of PD98059, a mitogen-activated protein kinase kinase kinase (MEK) inhibitor, confirmed the requirement for MEK in the activation of ERKs by HBx. Induction of ERK activity by HBx was sustained for up to 30 days. Interestingly, sustained activation of c-Jun N-terminal kinases (JNKs) for up to 30 days was also noted. Such constitutive ERK and JNK activation as a consequence of continued HBx expression also led to sustained stimulation of further downstream events, such as increased levels of c-Jun and c-Fos proteins along with the persistent induction of activator protein 1 binding activity. Taken together, our data suggest a critical role of these molecules in HBx-mediated cell transformation.

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Stimulation of Cellular Proliferation by Hepatitis B Virus X Protein

Disease Markers ◽

10.1155/2001/571254 ◽

2001 ◽

Vol 17 (3) ◽

pp. 153-157 ◽

Cited By ~ 47

Author(s):

Charles R. Madden ◽

Betty L. Slagle

Keyword(s):

Hepatitis B Virus ◽

Hepatitis B ◽

Cellular Proliferation ◽

X Protein ◽

Hepatitis Viruses ◽

B Virus ◽

Infected Cells ◽

Proliferation In Vitro

Chronic infection with the hepatitis B virus (HBV) is a known risk factor in the development of human hepatocellular carcinoma (HCC). The HBV-encoded X protein, HBx, has been investigated for properties that may explain its cancer cofactor role in transgenic mouse lines. We discuss here recent data showing that HBx is able to induce hepatocellular proliferation in vitro and in vivo. This property of HBx is predicted to sensitize hepatocytes to other HCC cofactors, including exposure to carcinogens and to other hepatitis viruses. Cellular proliferation is intimately linked to the mechanism(s) by which most tumor-associated viruses transform virus-infected cells. The HBx alteration of the cell cycle provides an additional mechanism by which chronic HBV infection may contribute to HCC.

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Hepatitis B Virus X Protein Is both a Substrate and a Potential Inhibitor of the Proteasome Complex

Journal of Virology ◽

10.1128/jvi.73.9.7231-7240.1999 ◽

1999 ◽

Vol 73 (9) ◽

pp. 7231-7240 ◽

Cited By ~ 157

Author(s):

Zongyi Hu ◽

Zhensheng Zhang ◽

Edward Doo ◽

Olivier Coux ◽

Alfred L. Goldberg ◽

...

Keyword(s):

Hepatitis B Virus ◽

Hepatitis B ◽

Gradient Centrifugation ◽

Proteasome Inhibitors ◽

Hbv Infection ◽

26S Proteasome ◽

Viral Gene ◽

X Protein ◽

B Virus

ABSTRACT The hepatitis B virus X protein (HBX) is essential for the establishment of HBV infection in vivo and exerts a pleiotropic effect on diverse cellular functions. The yeast two-hybrid system had indicated that HBX could interact with two subunits of the 26S proteasome. Here we demonstrate an association in vivo of HBX with the 26S proteasome complex by coimmunoprecipitation and colocalization upon sucrose gradient centrifugation. Expression of HBX in HepG2 cells caused a modest decrease in the proteasome’s chymotrypsin- and trypsin-like activities and in hydrolysis of ubiquitinated lysozyme, suggesting that HBX functions as an inhibitor of proteasome. In these cells, HBX is degraded with a half-life of 30 min. Proteasome inhibitors retarded this rapid degradation and caused a marked increase in the level of HBX and an accumulation of HBX in polyubiquitinated form. Thus, the low intracellular level of HBX is due to rapid proteolysis by the ubiquitin-proteasome pathway. Surprisingly, the proteasome inhibitors blocked the transactivation by HBX, and this effect was not a result of a squelching phenomenon due to HBX accumulation. Therefore, proteasome function is possibly required for the transactivation function of HBX. The inhibition of protein breakdown by proteasomes may account for the multiple actions of HBX and may be an important feature of HBV infection, possibly in helping stabilize viral gene products and suppressing antigen presentation.

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