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Article

Antiviral therapy may decrease HBx, affecting cccDNA and MSL2 in hepatocarcinogenesis

  • Authors:
    • Xue‑Li Jin
    • Suk Kyun Hong
    • Hwajung Kim
    • Sun‑Kyung Lee
    • Nam‑Joon Yi
    • Kwang‑Woong Lee
    • Kyung‑Suk Suh
  • View Affiliations / Copyright

    Affiliations: Department of Surgery, Seoul National University College of Medicine, Seoul 03080, Republic of Korea
  • Pages: 4984-4991
    |
    Published online on: September 10, 2019
       https://doi.org/10.3892/ol.2019.10833
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Abstract

Chronic hepatitis B virus (HBV) is the leading cause of hepatocellular carcinoma (HCC). Covalently closed circular DNA (cccDNA) is an intermediate in the life cycle of HBV. HBV‑encoded X protein (HBx), a key viral oncoprotein, can be specifically ubiquitylated by male specific lethal 2 (MSL2), which causes upregulation of HBx activity and promotes transcription, cell proliferation and tumor growth. The present study compared the levels of cccDNA, MSL2 mRNA and HBx mRNA in tumor and peri‑tumor tissues, and clarified the effect of antiviral therapy on these indicators. Levels of intrahepatic cccDNA, MSL2 mRNA and HBx mRNA were determined using quantitative PCR in patients with HBV‑associated HCC who had undergone liver surgery. A total of 50 patients were included in the present study. Prior to surgery, 31 patients had undergone antiviral treatment. Intrahepatic cccDNA levels were significantly higher in the tumor tissues compared with the peri‑tumor tissues (P=0.001), particularly in the hepatitis B e antigen‑positive (P=0.008), tumor recurrence (P=0.002) and <3 cm tumor size (P=0.003) groups. Furthermore, in patients with preoperative cirrhosis, levels of cccDNA and MSL2 mRNA were significantly higher in tumor tissues compared with that in peri‑tumor tissues (P<0.001 and P=0.023, respectively). The expression levels of HBx mRNA in antiviral‑treated tumors and peri‑tumor tissues were significantly lower compared with those in untreated tissues (P=0.026 and P=0.035). The levels of cccDNA and MSL2 mRNA in the HBx‑positive group were significantly higher in tumor tissues compared with those in peri‑tumor tissues (P=0.026 and P=0.013). In conclusion, cccDNA participated in the tumorigenesis of HBV‑associated HCC, and antiviral therapy was found to modulate hepatocarcinogenesis by decreasing the levels of HBx to inhibit the tumorigenic effect of MSL2 and cccDNA.
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1 

Aljarbou AN: The emergent concern of Hepatitis B globally with special attention to Kingdom of Saudi Arabia. Int J Health Sci (Qassim). 7:333–340. 2013. View Article : Google Scholar : PubMed/NCBI

2 

Allweiss L and Dandri M: The role of cccDNA in HBV maintenance. Viruses. 9(pii): E1562017. View Article : Google Scholar : PubMed/NCBI

3 

Lupberger J and Hildt E: Hepatitis B virus-induced oncogenesis. World J Gastroenterol. 13:74–81. 2007. View Article : Google Scholar : PubMed/NCBI

4 

Blum HE: Hepatocellular carcinoma: Therapy and prevention. World J Gastroenterol. 11:7391–7400. 2005.PubMed/NCBI

5 

Wu M, Li J, Yue L, Bai L, Li Y, Chen J, Zhang X and Yuan Z: Establishment of Cre-mediated HBV recombinant cccDNA (rcccDNA) cell line for cccDNA biology and antiviral screening assays. Antiviral Res. 152:45–52. 2018. View Article : Google Scholar : PubMed/NCBI

6 

Mazet-Wagner AA, Baclet MC, Loustaud-Ratti V, Denis F and Alain S: Real-time PCR quantitation of hepatitis B virus total DNA and covalently closed circular DNA in peripheral blood mononuclear cells from hepatitis B virus-infected patients. J Virol Methods. 138:70–79. 2006. View Article : Google Scholar : PubMed/NCBI

7 

Wong DK, Yuen MF, Yuan H, Sum SS, Hui CK, Hall J and Lai CL: Quantitation of covalently closed circular hepatitis B virus DNA in chronic hepatitis B patients. Hepatology. 40:727–737. 2004. View Article : Google Scholar : PubMed/NCBI

8 

Ng SA and Lee C: Hepatitis B virus X gene and hepatocarcinogenesis. J Gastroenterol. 46:974–990. 2011. View Article : Google Scholar : PubMed/NCBI

9 

Zhang X, Zhang H and Ye L: Effects of hepatitis B virus X protein on the development of liver cancer. J Lab Clin Med. 147:58–66. 2006. View Article : Google Scholar : PubMed/NCBI

10 

Ding R, Han S, Lu Y, Guo C, Xie H, Zhang N, Song Z, Cai L, Liu J and Dou K: Overexpressed Id-1 is associated with patient prognosis and HBx expression in hepatitis B virus-related hepatocellular carcinoma. Cancer Biol Ther. 10:299–307. 2010. View Article : Google Scholar : PubMed/NCBI

11 

Rabut G and Peter M: Function and regulation of protein neddylation. ‘Protein modifications: Beyond the usual suspects’ review series. EMBO Rep. 9:969–976. 2008. View Article : Google Scholar : PubMed/NCBI

12 

Villa R, Forne I, Muller M, Imhof A, Straub T and Becker PB: MSL2 combines sensor and effector functions in homeostatic control of the Drosophila dosage compensation machinery. Mol Cell. 48:647–654. 2012. View Article : Google Scholar : PubMed/NCBI

13 

Gao Y, Feng J, Yang G, Zhang S, Liu Y, Bu Y, Sun M, Zhao M, Chen F, Zhang W, et al: Hepatitis B virus X protein-elevated MSL2 modulates hepatitis B virus covalently closed circular DNA by inducing degradation of APOBEC3B to enhance hepatocarcinogenesis. Hepatology. 66:1413–1429. 2017. View Article : Google Scholar : PubMed/NCBI

14 

Bowden S, Jackson K, Littlejohn M and Locarnini S: Quantification Of HBV covalently closed circular DNA from liver tissue by real-time PCR. Methods Mol Med. 95:41–50. 2004.PubMed/NCBI

15 

Livak KJ and Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) method. Methods. 25:402–408. 2001. View Article : Google Scholar : PubMed/NCBI

16 

Duan BW, Lu SC, Lai W, Liu XE and Liu Y: The detection of (total and ccc) HBV DNA in liver transplant recipients with hepatitis B vaccine against HBV reinfection. Hum Vaccin Immunother. 11:2490–2494. 2015. View Article : Google Scholar : PubMed/NCBI

17 

Kim JW, Lee SH, Park YS, Hwang JH, Jeong SH, Kim N and Lee DH: Replicative activity of hepatitis B virus is negatively associated with methylation of covalently closed circular DNA in advanced hepatitis B virus infection. Intervirology. 54:316–325. 2011. View Article : Google Scholar : PubMed/NCBI

18 

Schreiner S and Nassal M: A role for the Host DNA damage response in hepatitis B virus cccDNA formation-and beyond? Viruses. 9(pii): E1252017. View Article : Google Scholar : PubMed/NCBI

19 

Fu S, Li N, Zhou PC, Huang Y, Zhou RR and Fan XG: Detection of HBV DNA and antigens in HBsAg-positive patients with primary hepatocellular carcinoma. Clin Res Hepatol Gastroenterol. 41:415–423. 2017. View Article : Google Scholar : PubMed/NCBI

20 

Chuaypen N, Sriprapun M, Praianantathavorn K, Payungporn S, Wisedopas N, Poovorawan Y and Tangkijvanich P: Kinetics of serum HBsAg and intrahepatic cccDNA during pegylated interferon therapy in patients with HBeAg-positive and HBeAg-negative chronic hepatitis B. J Med Virol. 89:130–138. 2017. View Article : Google Scholar : PubMed/NCBI

21 

Pichoud C, Berby F, Stuyver L, Petit MA, Trepo C and Zoulim F: Persistence of viral replication after anti-HBe seroconversion during antiviral therapy for chronic hepatitis B. J Hepatol. 32:307–316. 2000. View Article : Google Scholar : PubMed/NCBI

22 

Roche B, Feray C, Gigou M, Roque-Afonso AM, Arulnaden JL, Delvart V, Dussaix E, Guettier C, Bismuth H and Samuel D: HBV DNA persistence 10 years after liver transplantation despite successful anti-HBS passive immunoprophylaxis. Hepatology. 38:86–95. 2003. View Article : Google Scholar : PubMed/NCBI

23 

Suzuki F, Miyakoshi H, Kobayashi M and Kumada H: Correlation between serum hepatitis B virus core-related antigen and intrahepatic covalently closed circular DNA in chronic hepatitis B patients. J Med Virol. 81:27–33. 2009. View Article : Google Scholar : PubMed/NCBI

24 

Chauhan R, Lingala S, Gadiparthi C, Lahiri N, Mohanty SR, Wu J, Michalak TI and Satapathy SK: Reactivation of hepatitis B after liver transplantation: Current knowledge, molecular mechanisms and implications in management. World J Hepatol. 10:352–370. 2018. View Article : Google Scholar : PubMed/NCBI

25 

Song GW, Ahn CS, Lee SG, Hwang S, Kim KH, Moon DB, Ha TY, Jung DH, Park GC, Kang SH, et al: Correlation between risk of hepatitis B virus recurrence and tissue expression of covalently closed circular DNA in living donor liver transplant recipients treated with high-dose hepatitis B immunoglobulin. Transplant Proc. 46:3548–3553. 2014. View Article : Google Scholar : PubMed/NCBI

26 

Nguyen MH and Keeffe EB: Are hepatitis B e antigen (HBeAg)-positive chronic hepatitis B and HBeAg-negative chronic hepatitis B distinct diseases? Clin Infect Dis. 47:1312–1314. 2008. View Article : Google Scholar : PubMed/NCBI

27 

Ganem D and Prince AM: Hepatitis B virus infection-natural history and clinical consequences. N Engl J Med. 350:1118–29. 2004. View Article : Google Scholar : PubMed/NCBI

28 

Wang Q, Lin L, Yoo S, Wang W, Blank S, Fiel MI, Kadri H, Luan W, Warren L, Zhu J and Hiotis SP: Impact of non-neoplastic vs intratumoural hepatitis B viral DNA and replication on hepatocellular carcinoma recurrence. Br J Cancer. 115:841–847. 2016. View Article : Google Scholar : PubMed/NCBI

29 

Yang HI, Lu SN, Liaw YF, You SL, Sun CA, Wang LY, Hsiao CK, Chen PJ, Chen DS and Chen CJ; Taiwan Community-Based Cancer Screening Project Group, : Hepatitis B e antigen and the risk of hepatocellular carcinoma. N Engl J Med. 347:168–174. 2002. View Article : Google Scholar : PubMed/NCBI

30 

Sun HC, Zhang W, Qin LX, Zhang BH, Ye QH, Wang L, Ren N, Zhuang PY, Zhu XD, Fan J and Tang ZY: Positive serum hepatitis B e antigen is associated with higher risk of early recurrence and poorer survival in patients after curative resection of hepatitis B-related hepatocellular carcinoma. J Hepatol. 47:684–690. 2007. View Article : Google Scholar : PubMed/NCBI

31 

Kubo S, Hirohashi K, Yamazaki O, Matsuyama M, Tanaka H, Horii K, Shuto T, Yamamoto T, Kawai S, Wakasa K, et al: Effect of the presence of hepatitis B e antigen on prognosis after liver resection for hepatocellular carcinoma in patients with chronic hepatitis B. World J Surg. 26:555–560. 2002. View Article : Google Scholar : PubMed/NCBI

32 

Shirabe K, Kanematsu T, Matsumata T, Adachi E, Akazawa K and Sugimachi K: Factors linked to early recurrence of small hepatocellular carcinima after hepatectomy: Univariate and multivarate analysis. Hepatology. 14:802–805. 1991. View Article : Google Scholar : PubMed/NCBI

33 

Jiao F, Long L, Ding S, Xie X, Jia L and Lu F: Complete genome sequencing and clinical analysis of intrahepatic hepatitis B virus cccDNA from HCC. Microb Pathog. 109:49–55. 2017. View Article : Google Scholar : PubMed/NCBI

34 

Yang G, Han M, Chen F, Xu Y, Chen E, Wang X, Liu Y, Sun J, Hou J, Ning Q and Wang Z: Hepatitis B virus genotype B and mutations in basal core promoter and pre-core/core genes associated with acute-on-chronic liver failure: A multicenter cross-sectional study in China. Hepatol Int. 8:508–516. 2014. View Article : Google Scholar : PubMed/NCBI

35 

Xu H, Zhao M, Lou G, Zheng M, Cao Q and Chen Z: New point mutations in surface and core genes of hepatitis B virus associated with acute on chronic liver failure identified by complete genomic sequencing. PLoS One. 10:e01231392015. View Article : Google Scholar : PubMed/NCBI

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Copy and paste a formatted citation
Spandidos Publications style
Jin XL, Hong SK, Kim H, Lee SK, Yi NJ, Lee KW and Suh KS: Antiviral therapy may decrease HBx, affecting cccDNA and MSL2 in hepatocarcinogenesis. Oncol Lett 18: 4984-4991, 2019.
APA
Jin, X., Hong, S.K., Kim, H., Lee, S., Yi, N., Lee, K., & Suh, K. (2019). Antiviral therapy may decrease HBx, affecting cccDNA and MSL2 in hepatocarcinogenesis. Oncology Letters, 18, 4984-4991. https://doi.org/10.3892/ol.2019.10833
MLA
Jin, X., Hong, S. K., Kim, H., Lee, S., Yi, N., Lee, K., Suh, K."Antiviral therapy may decrease HBx, affecting cccDNA and MSL2 in hepatocarcinogenesis". Oncology Letters 18.5 (2019): 4984-4991.
Chicago
Jin, X., Hong, S. K., Kim, H., Lee, S., Yi, N., Lee, K., Suh, K."Antiviral therapy may decrease HBx, affecting cccDNA and MSL2 in hepatocarcinogenesis". Oncology Letters 18, no. 5 (2019): 4984-4991. https://doi.org/10.3892/ol.2019.10833
Copy and paste a formatted citation
x
Spandidos Publications style
Jin XL, Hong SK, Kim H, Lee SK, Yi NJ, Lee KW and Suh KS: Antiviral therapy may decrease HBx, affecting cccDNA and MSL2 in hepatocarcinogenesis. Oncol Lett 18: 4984-4991, 2019.
APA
Jin, X., Hong, S.K., Kim, H., Lee, S., Yi, N., Lee, K., & Suh, K. (2019). Antiviral therapy may decrease HBx, affecting cccDNA and MSL2 in hepatocarcinogenesis. Oncology Letters, 18, 4984-4991. https://doi.org/10.3892/ol.2019.10833
MLA
Jin, X., Hong, S. K., Kim, H., Lee, S., Yi, N., Lee, K., Suh, K."Antiviral therapy may decrease HBx, affecting cccDNA and MSL2 in hepatocarcinogenesis". Oncology Letters 18.5 (2019): 4984-4991.
Chicago
Jin, X., Hong, S. K., Kim, H., Lee, S., Yi, N., Lee, K., Suh, K."Antiviral therapy may decrease HBx, affecting cccDNA and MSL2 in hepatocarcinogenesis". Oncology Letters 18, no. 5 (2019): 4984-4991. https://doi.org/10.3892/ol.2019.10833
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