Abstract
The function of the hepatitis B virus X protein (HBx) has been investigated in hepatoma cell lines before; however, its function in the canonical HEK 293 cell line has not been addressed. In this study, we found that HBx increased cellular interaction by fusing the gap between HEK 293 cells, which is different from what has been reported previously. We also found that HBx enhanced the expression of E-cadherin in hepatoma cell lines instead of decreasing it as reported previously. The increase in E-cadherin was mediated by the enhanced levels of Src, which also differs from previous reports. Finally, we observed that HBx can accelerate cell growth by increasing the percentage of cells that are positioned at the division stage. Further analysis showed that the increased growth was caused by increased CDK4 expression and Ki67+ populations. Additionally, reduced apoptosis was found in HEK 293 cells expressing HBx due to an increase in the anti-apoptotic protein-Bcl2. Collectively, the different functions of HBx in HEK 293 cells suggest that its role is cell dependent.
References
Ahn JY, Jung EY, Kwun HJ, Lee CW, Sung YC, Jang KL (2002) Dual effects of hepatitis B virus X protein on the regulation of cell-cycle control depending on the status of cellular p53. J Gen Virol 83:2765–2772
Arzumanyan A, Friedman T, Kotei E, Ng IO, Lian Z, Feitelson MA (2012) Epigenetic repression of E-cadherin expression by hepatitis B virus × antigen in liver cancer. Oncogene 31:563–572
Beck J, Nassal M (2007) Hepatitis B virus replication. WJG 13:48–64
Blumberg BS, Millman I, Venkateswaran PS, Thyagarajan SP (1989) Hepatitis B virus and hepatocellular carcinoma–treatment of HBV carriers with Phyllanthus amarus. Cancer Detect Prev 14:195–201
Byeon IJ, Li H, Song H, Gronenborn AM, Tsai MD (2005) Sequential phosphorylation and multisite interactions characterize specific target recognition by the FHA domain of Ki67. Nat Struct Mol Biol 12:987–993
Fung SK, Lok AS (2004) Viral hepatitis in 2003. Curr Opin Gastroenterol 20:241–247
Hirohashi S (1998) Inactivation of the E-cadherin-mediated cell adhesion system in human cancers. Am J Pathol 153:333–339
Hirohashi S, Kanai Y (2003) Cell adhesion system and human cancer morphogenesis. Cancer Sci 94:575–581
Kay A, Zoulim F (2007) Hepatitis B virus genetic variability and evolution. Virus Res 127:164–176
Klein NP, Schneider RJ (1997) Activation of Src family kinases by hepatitis B virus HBx protein and coupled signaling to Ras. Mol Cell Biol 17:6427–6436
Lara-Pezzi E, Roche S, Andrisani OM, Sanchez-Madrid F, Lopez-Cabrera M (2001) The hepatitis B virus HBx protein induces adherens junction disruption in a src-dependent manner. Oncogene 20:3323–3331
Lee JO, Kwun HJ, Jung JK, Choi KH, Min DS, Jang KL (2005) Hepatitis B virus X protein represses E-cadherin expression via activation of DNA methyltransferase 1. Oncogene 24:6617–6625
Li T, Robert EI, van Breugel PC, Strubin M, Zheng N (2010) A promiscuous alpha-helical motif anchors viral hijackers and substrate receptors to the CUL4-DDB1 ubiquitin ligase machinery. Nat Struct Mol Biol 17:105–111
Li W, Miao X, Qi Z, Zeng W, Liang J, Liang Z (2010) Hepatitis B virus X protein upregulates HSP90alpha expression via activation of c-Myc in human hepatocarcinoma cell line, HepG2. Virol J 7:45
Liu C, Miller H, Hui KL, Grooman B, Bolland S, Upadhyaya A, Song W (2011) A balance of Bruton’s tyrosine kinase and SHIP activation regulates B cell receptor cluster formation by controlling actin remodeling. J Immunol 187:230–239
Liu C, Bai X, Wu J, Sharma S, Upadhyaya A, Dahlberg CI, Westerberg LS, Snapper SB, Zhao X, Song W (2013) N-wasp is essential for the negative regulation of B cell receptor signaling. PLoS Biol 11:e1001704
Liu C, Wang Y, Wu C, Pei R, Song J, Chen S, Chen X (2013) Dioscin’s antiviral effect in vitro. Virus Res 172:9–14
Martin SJ, Reutelingsperger CP, McGahon AJ, Rader JA, van Schie RC, LaFace DM, Green DR (1995) Early redistribution of plasma membrane phosphatidylserine is a general feature of apoptosis regardless of the initiating stimulus: inhibition by overexpression of Bcl-2 and Abl. J Exp Med 182:1545–1556
Poligone B, Gilmore ES, Alexander CV, Oleksyn D, Gillespie K, Zhao J, Ibrahim SF, Pentland AP, Brown MD, Chen L (2015) PKK suppresses tumor growth and is decreased in squamous cell carcinoma of the skin. J Invest Dermatol 135:869–876
Schmid I, Krall WJ, Uittenbogaart CH, Braun J, Giorgi JV (1992) Dead cell discrimination with 7-amino-actinomycin D in combination with dual color immunofluorescence in single laser flow cytometry. Cytometry 13:204–208
Wang XW, Forrester K, Yeh H, Feitelson MA, Gu JR, Harris CC (1994) Hepatitis B virus X protein inhibits p53 sequence-specific DNA binding, transcriptional activity, and association with transcription factor ERCC3. Proc Natl Acad Sci USA 91:2230–2234
Wen Y, Golubkov VS, Strongin AY, Jiang W, Reed JC (2008) Interaction of hepatitis B viral oncoprotein with cellular target HBXIP dysregulates centrosome dynamics and mitotic spindle formation. J Biol Chem 283:2793–2803
Acknowledgments
We thank Drs. Vera Stupina and Megan Young for critically reading the manuscript. This work was supported by a project from Chongqing Science and Technology Commission (cstc2015shmszx0196). The authors have no conflicts of interest to declare. This article does not contain any studies with human participants or animals performed by any of the authors.
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Zhang, Y., Cheng, J. & Liu, C. The unique role of the hepatitis virus B X protein on HEK 293 cell morphology and cellular change. Arch Virol 161, 1347–1352 (2016). https://doi.org/10.1007/s00705-016-2786-y
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DOI: https://doi.org/10.1007/s00705-016-2786-y