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Peroxisome-localized hepatitis Bx protein increases the invasion property of hepatocellular carcinoma cells

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Abstract

HBx acts as a multifunctional regulator that modulates various cellular responses, which can lead to development and progression of hepatocellular carcinoma (HCC). Here, we show that the HBx protein is also localized to peroxisomes, and this increases cellular reactive oxygen species (ROS) to levels that are higher than when HBx is localized to other organelles. The elevated ROS strongly activated nuclear factor (NF)-κB. In addition, the peroxisome-localized HBx increased the expressions of matrix metalloproteinases and decreased the expression of E-cadherin, which increased the invasive ability of HCC cells. Thus, a specific distribution of HBx to peroxisomes may contribute to HCC progression by increasing the invasive ability of HCC cells through elevation of the cellular ROS level.

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Abbreviations

HBV:

Hepatitis B virus

HCC:

Hepatocellular carcinoma

AP-1:

Activation protein-1

NF-κB:

Nuclear factor κB

ROS:

Reactive oxygen species

MMPs:

Matrix metalloproteinases

HA:

Hemagglutinin

FIS1:

Mitochondrial fission 1 protein

mAb:

Monoclonal antibody

pAb:

Polyclonal antibody

DMEM:

Dulbecco’s modified Eagle’s medium

FBS:

Fetal bovine serum

SDS:

Sodium dodecyl sulfate

PBS:

Phosphate-buffered saline

IRES:

Internal ribosome entry site

GFP:

Green fluorescent protein

RT-PCR:

Reverse transcription polymerase chain reaction

GAPDH:

Glyceraldehyde-3-phosphate dehydrogenase

MAVS:

Mitochondrial antiviral signaling

NAC:

N-Acetyl cysteine

PEX5:

Peroxisomal biogenesis factor 5

References

  1. Baes M, Gressens P, Baumgart E, Carmeliet P, Casteels M, Fransen M, Evrard P, Fahimi D, Declercq PE, Collen D, van Veldhoven PP, Mannaerts GP (1997) A mouse model for Zellweger syndrome. Nat Genet 17:49–57

    Article  PubMed  CAS  Google Scholar 

  2. Chung TW, Lee YC, Kim CH (2004) Hepatitis B viral HBx induces matrix metalloproteinase-9 gene expression through activation of ERK and PI-3K/AKT pathways: involvement of invasive potential. FASEB J 18:1123–1125

    Article  PubMed  CAS  Google Scholar 

  3. Clippinger AJ, Bouchard MJ (2008) Hepatitis B virus HBx protein localizes to mitochondria in primary rat hepatocytes and modulates mitochondrial membrane potential. J Virol 82:6798–6811

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  4. Delille HK, Alves R, Schrader M (2009) Biogenesis of peroxisomes and mitochondria: linked by division. Histochem Cell Biol 131:441–446

    Article  PubMed  CAS  Google Scholar 

  5. Dixit E, Boulant S, Zhang Y, Lee AS, Odendall C, Shum B, Hacohen N, Chen ZJ, Whelan SP, Fransen M, Nibert ML, Superti-Furga G, Kagan JC (2010) Peroxisomes are signaling platforms for antiviral innate immunity. Cell 141:668–681

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  6. Jeong SP, Kang JA, Park SG (2012) Intestinal intraepithelial TCRgammadelta(+) T cells are activated by normal commensal bacteria. J Microbiol 50:837–841

    Article  PubMed  Google Scholar 

  7. Kim CM, Koike K, Saito I, Miyamura T, Jay G (1991) HBx gene of hepatitis B virus induces liver cancer in transgenic mice. Nature 351:317–320

    Article  PubMed  CAS  Google Scholar 

  8. Kim SY, Lee PY, Shin HJ, Kim do H, Kang S, Moon HB, Kang SW, Kim JM, Park SG, Park BC, Yu DY, Bae KH, Lee SC (2009) Proteomic analysis of liver tissue from HBx-transgenic mice at early stages of hepatocarcinogenesis. Proteomics 9:5056–5066

    Article  PubMed  CAS  Google Scholar 

  9. Kumar M, Jung SY, Hodgson AJ, Madden CR, Qin J, Slagle BL (2011) Hepatitis B virus regulatory HBx protein binds to adaptor protein IPS-1 and inhibits the activation of beta interferon. J Virol 85:987–995

    Article  PubMed  PubMed Central  Google Scholar 

  10. Lim SO, Gu JM, Kim, Kim HS, Park YN, Park CK, Cho JW, Park YM, Jung G (2008) Epigenetic changes induced by reactive oxygen species in hepatocellular carcinoma: methylation of the E-cadherin promoter. Gastroenterology 135:2128–2140 (2140 e2121–2128)

    Article  PubMed  CAS  Google Scholar 

  11. Liu LP, Liang HF, Chen XP, Zhang WG, Yang SL, Xu T, Ren L (2010) The role of NF-kappaB in Hepatitis b virus X protein-mediated upregulation of VEGF and MMPs. Cancer Investig 28:443–451

    Article  CAS  Google Scholar 

  12. Liu Y, Tong Z, Li T, Chen Q, Zhuo L, Li W, Wu RC, Yu C (2012) Hepatitis B virus X protein stabilizes amplified in breast cancer 1 protein and cooperates with it to promote human hepatocellular carcinoma cell invasiveness. Hepatology 56:1015–1024

    Article  PubMed  CAS  Google Scholar 

  13. Liu YN, Lee WW, Wang CY, Chao TH, Chen Y, Chen JH (2005) Regulatory mechanisms controlling human E-cadherin gene expression. Oncogene 24:8277–8290

    Article  PubMed  CAS  Google Scholar 

  14. Ma J, Sun T, Park S, Shen G, Liu J (2011) The role of hepatitis B virus X protein is related to its differential intracellular localization. Acta biochimica et biophysica Sinica 43:583–588

    Article  PubMed  CAS  Google Scholar 

  15. Morgan MJ, Liu ZG (2011) Crosstalk of reactive oxygen species and NF-kappaB signaling. Cell Res 21:103–115

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  16. Ng SA, Lee C (2011) Hepatitis B virus X gene and hepatocarcinogenesis. J Gastroenterol 46:974–990

    Article  PubMed  CAS  Google Scholar 

  17. Park SG, Ryu HM, Lim SO, Kim YI, Hwang SB, Jung G (2005) Interferon-gamma inhibits hepatitis B virus-induced NF-kappaB activation through nuclear localization of NF-kappaB-inducing kinase. Gastroenterology 128:2042–2053

    Article  PubMed  CAS  Google Scholar 

  18. Park SG, Chung C, Kang H, Kim JY, Jung G (2006) Up-regulation of cyclin D1 by HBx is mediated by NF-kappaB2/BCL3 complex through kappaB site of cyclin D1 promoter. J Biol Chem 281:31770–31777

    Article  PubMed  CAS  Google Scholar 

  19. Schrader M, Fahimi HD (2004) Mammalian peroxisomes and reactive oxygen species. Histochem Cell Biol 122:383–393

    Article  PubMed  CAS  Google Scholar 

  20. Schrader M, Fahimi HD (2006) Peroxisomes and oxidative stress. Biochimica et biophysica acta 1763:1755–1766

    Article  PubMed  CAS  Google Scholar 

  21. Tang H, Oishi N, Kaneko S, Murakami S (2006) Molecular functions and biological roles of hepatitis B virus x protein. Cancer Sci 97:977–983

    Article  PubMed  CAS  Google Scholar 

  22. Trachootham D, Alexandre J, Huang P (2009) Targeting cancer cells by ROS-mediated mechanisms: a radical therapeutic approach? Nat Rev Drug Discov 8:579–591

    Article  PubMed  CAS  Google Scholar 

  23. Wanders RJ, Waterham HR (2006) Biochemistry of mammalian peroxisomes revisited. Annu Rev Biochem 75:295–332

    Article  PubMed  CAS  Google Scholar 

  24. Waris G, Huh KW, Siddiqui A (2001) Mitochondrially associated hepatitis B virus X protein constitutively activates transcription factors STAT-3 and NF-kappa B via oxidative stress. Mol Cellular Biol 21:7721–7730

    Article  CAS  Google Scholar 

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Acknowledgments

This work was supported by a grant of the Korean Health Technology R&D Project, Ministry of Health & Welfare, Republic of Korea (A111838) and by the National Research Foundation of Korea (NRF), funded by the Ministry of Education, Science and Technology (MEST)(NRF-2013R1A1A2010995).

Conflict of interest

We confirm that all authors fulfill all conditions required for authorship. We also confirm that there is no potential conflict of interest or financial dependence regarding this publication, as described in the Instructions for Authors. All authors have read and approved the manuscript.

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Authors and Affiliations

  1. School of Life Sciences, Gwangju Institute of Science and Technology (GIST), Gwangju, Republic of Korea

    Jae-Min Han, Jung-Ah Kang, Min-Hee Han, Kyung-Hun Chung, Cho-Rong Lee, Woo-Keun Song, Youngsoo Jun & Sung-Gyoo Park

  2. Immune Synapse Research Center, Gwangju Institute of Science and Technology (GIST), Gwangju, Republic of Korea

    Jae-Min Han, Jung-Ah Kang, Min-Hee Han, Cho-Rong Lee, Youngsoo Jun & Sung-Gyoo Park

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  1. Jae-Min Han
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  2. Jung-Ah Kang
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  3. Min-Hee Han
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  4. Kyung-Hun Chung
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  5. Cho-Rong Lee
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  8. Sung-Gyoo Park
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Correspondence to Sung-Gyoo Park.

Additional information

J.-M. Han and J.-A. Kang contributed equally to this paper

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Han, JM., Kang, JA., Han, MH. et al. Peroxisome-localized hepatitis Bx protein increases the invasion property of hepatocellular carcinoma cells. Arch Virol 159, 2549–2557 (2014). https://doi.org/10.1007/s00705-014-2105-4

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  • DOI: https://doi.org/10.1007/s00705-014-2105-4

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