Role of STAT1 in the resistance of HBV to IFN‑α

Xu,Bingfa; Tang,Bo; Wei,Jiajia

doi:10.3892/etm.2021.9982

Role of STAT1 in the resistance of HBV to IFN‑α

Authors:
- Bingfa Xu
- Bo Tang
- Jiajia Wei
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Affiliations: Department of Pharmacy, The Third Affiliated Hospital of Anhui Medical University, Hefei, Anhui 230061, P.R. China, Department of Pharmacy, Huainan First People's Hospital, Huainan, Anhui 232007, P.R. China, Department of Pharmacy, The First People's Hospital of Changzhou, Changzhou, Jiangsu 213000, P.R. China
Published online on: March 24, 2021 https://doi.org/10.3892/etm.2021.9982
Article Number: 550
Copyright: © Xu et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

The objective of the present study was to explore the mechanism of hepatitis B virus (HBV) resistance to interferon (IFN), and the role of signal transducer and activator of transcription 1 (STAT1). HepG2.2.15 cells were stimulated with a long‑term (6‑24 weeks) low‑dose interferon (IFN)α‑2b (10‑70 IU/ml), so as to construct and screen a HepG2.2.15 cell model resistant to IFNα‑2b. The changes of STAT1 and other proteins in the JAK‑STAT signaling pathway, before and after drug resistance, were compared. The phosphorylation of STAT1 in HepG2.2.15 cells resistant to IFNα‑2b was significantly decreased, and the expression level of 2',5'‑oligoadenylate synthetase 1 was downregulated. Decreased phosphorylation of STAT1 in the JAK‑STAT signaling pathway a contributor to the development of resistance to IFN‑α in HBV.

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1	Woo HG, Kim SS, Cho H, Kwon SM, Cho HJ, Ahn SJ, Park ES, Lee JS, Cho SW and Cheong JY: Profiling of exome mutations associated with progression of HBV-related hepatocellular carcinoma. PLoS One. 9(e115152)2014.PubMed/NCBI View Article : Google Scholar
2	Schweitzer A, Horn J, Mikolajczyk RT, Krause G and Ott JJ: Estimations of worldwide prevalence of chronic hepatitis B virus infection: A systematic review of data published between 1965 and 2013. Lancet. 386:1546–1555. 2015.PubMed/NCBI View Article : Google Scholar
3	Cho H and Kelsall BL: The role of type I interferons in intestinal infection, homeostasis, and inflammation. Immunol Rev. 260:145–167. 2014.PubMed/NCBI View Article : Google Scholar
4	Terrault NA, Lok ASF, Mcmahon BJ, Chang KM, Hwang JP, Jonas MM, Brown RS Jr, Bzowej NH and Wong JB: Update on prevention, diagnosis, and treatment and of chronic hepatitis B: AASLD 2018 hepatitis B guidance. Hepatology. 67:1560–1599. 2018.PubMed/NCBI View Article : Google Scholar
5	Koumbi L: Current and future antiviral drug therapies of hepatitis B chronic infection. World J Hepatol. 7:1030–1040. 2015.PubMed/NCBI View Article : Google Scholar
6	Li H, Gade P, Xiao W and Kalvakolanu DV: The interferon signaling network and transcription factor C/EBP-beta. Cell Mol Immunol. 4:407–418. 2007.PubMed/NCBI
7	Mani SKK and Andrisani O: Interferon signaling during Hepatitis B Virus (HBV) infection and HBV-associated hepatocellular carcinoma. Cytokine. 124(154518)2019.PubMed/NCBI View Article : Google Scholar
8	Liongue C, O'Sullivan LA, Trengove MC and Ward AC: Evolution of JAK-STAT pathway component: Mechanisms and role in immune system development. PLoS One. 7(e32777)2012.PubMed/NCBI View Article : Google Scholar
9	O'Shea JJ and Plenge R: JAKs and STATs in immunoregulation and immune-mediated disease. Immunity. 36:542–550. 2012.PubMed/NCBI View Article : Google Scholar
10	Elli EM, Baratè C, Mendicino F, Palandri F and Palumbo GA: Mechanisms underlying the anti-inflammatory and immunosuppressive activity of ruxolitinib. Front Oncol. 9(1186)2019.PubMed/NCBI View Article : Google Scholar
11	Sanachai K, Mahalapbutr P, Choowongkomon K, Poo-Arporn RP, Wolschann P and Rungrotmongkol T: Insights into the binding recognition and susceptibility of tofacitinib toward janus kinases. ACS Omega. 5:369–377. 2020.PubMed/NCBI View Article : Google Scholar
12	Rashid S, Bibi N, Parveen Z and Shafique S: Inhibition of Janus kinases by tyrosine phosphorylation inhibitor, Tyrphostin AG-490. J Biomol Struct Dyn. 33:2368–2379. 2015.PubMed/NCBI View Article : Google Scholar
13	Huang C, Cao J, Huang KJ, Zhang F, Jiang T, Zhu L and Qiu ZJ: Inhibition of STAT3 activity with AG490 decreases the invasion of human pancreatic cancer cells in vitro. Cancer Sci. 97:1417–1423. 2010.
14	Aue A, Szelinski F, Weißenberg SY, Wiedemann A, Rose T, Lino AC and Dörner T: Elevated STAT1 expression but not phosphorylation in lupus B cells correlates with disease activity and increased plasmablast susceptibility. Rheumatology (Oxford). 59:3435–3442. 2020.PubMed/NCBI View Article : Google Scholar
15	Hazari S, Chandra PK, Poat B, Datta S, Garry RF, Foster TP, Kousoulas G, Wakita T and Dash S: Impaired antiviral activity of interferon alpha against hepatitis C virus 2a in Huh-7 cells with a defective Jak-Stat pathway. Virol J. 7(36)2010.PubMed/NCBI View Article : Google Scholar
16	Poat B, Hazari S, Chandra PK, Gunduz F, Balart LA, Alvarez X and Dash S: SH2 modified STAT1 induces HLA-I expression and improves IFN-γ signaling in IFN-α resistant HCV replicon cells. PLoS One. 5(e13117)2010.PubMed/NCBI View Article : Google Scholar
17	Nguyen NV, Tran JT and Sanchez DJ: HIV blocks Type I IFN signaling through disruption of STAT1 phosphorylation. Innate Immun. 24:490–500. 2018.PubMed/NCBI View Article : Google Scholar
18	Spange S, Wagner T, Heinzel T and Krämer OH: Acetylation of non-histone proteins modulates cellular signalling at multiple levels. Int J Biochem Cell Biol. 4:185–198. 2009.PubMed/NCBI View Article : Google Scholar
19	Krämer OH and Heinzel T: Phosphorylation-acetylation switch in the regulation of STAT1 signaling. Mol Cell Endocrinol. 315:40–48. 2010.PubMed/NCBI View Article : Google Scholar
20	Wen D, Wang J, Yan H, Chen J, Xia K, Liu J and Zhang A: Effect of radix trichosanthis and trichosanthin on hepatitis B virus in HepG2.2.15 cells. J Nanosci Nanotechnol. 15:2094–2098. 2015.PubMed/NCBI View Article : Google Scholar
21	Wei J, Tang Bo, Xu B, et al: Construction of interferon-resistant HBV cell model. Chin Pharm J. 52:832–837. 2017.
22	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.PubMed/NCBI View Article : Google Scholar
23	Lu YQ, Han JX, Qi P, Xu W, Zu YH and Zhu B: Rapid quantification of hepatitis B virus DNA by real-time PCR using efficient TaqMan probe and extraction of virus DNA. World J Gastroenterol. 12:7365–7370. 2006.PubMed/NCBI View Article : Google Scholar
24	Shaw T, Bartholomeusz A and Locarnini S: HBV drug resistance: Mechanisms, detection and interpretation. J Hepatol. 44:593–606. 2006.PubMed/NCBI View Article : Google Scholar
25	Férir G, Kaptein S, Neyts J and De Clercq E: Antiviral treatment of chronic hepatitis B virus infections: the past, the present and the future. Rev Med Virol. 18:19–34. 2008.PubMed/NCBI View Article : Google Scholar
26	Uchibori K, Kasamatsu A, Sunaga M, Yokota S, Sakurada T, Kobayashi E, Yoshikawa M, Uzawa K, Ueda S, Tanzawa H and Sato N: Establishment and characterization of two 5-fluorouracil-resistant hepatocellular carcinoma cell lines. Int J Oncol. 40:1005–1010. 2012.PubMed/NCBI View Article : Google Scholar
27	Tran HT, Lim YS and Hwang SB: Establishment of interferon alpha-resistant hepatitis C virus using cell culture system. FEBS Lett. 585:409–413. 2011.PubMed/NCBI View Article : Google Scholar
28	Hou ZH, Han QJ, Zhang C, Tian ZG and Zhang J: miR146a impairs the IFN-induced anti-HBV immune response by downregulating STAT1 in hepatocytes. Liver Int. 34:58–68. 2014.PubMed/NCBI View Article : Google Scholar
29	Li J, Chen F, Zheng M, Zhu H, Zhao D, Liu W, Liu W and Chen Z: Inhibition of STAT1 methylation is involved in the resistance of hepatitis B virus to Interferon alpha. Antiviral Res. 85:463–469. 2010.PubMed/NCBI View Article : Google Scholar
30	Chen K, Liu J, Liu S, Xia M, Zhang X, Han D, Jiang Y, Wang C and Cao X: Methyltransferase SETD2-mediated methylation of STAT1 is critical for interferon antiviral activity. Cell. 170:492–506, e14. 2017.PubMed/NCBI View Article : Google Scholar
31	Bing Y, Zhu S, Yu G, Li T, Liu W, Li C, Wang Y, Qi H, Guo T, Yuan Y, et al: Glucocorticoid-induced S-adenosylmethionine enhances the interferon signaling pathway by restoring STAT1 protein methylation in hepatitis B virus-infected cells. J Biol Chem. 289:32639–23655. 2014.PubMed/NCBI View Article : Google Scholar
32	Li L, Lei QS, Zhang SJ, Kong LN and Qin B: Suppression of USP18 potentiates the anti-HBV activity of interferon alpha in HepG2.2.15 cells via JAK/STAT signaling. PLoS One. 11(e0156496)2016.PubMed/NCBI View Article : Google Scholar
33	Krämer OH, Knauer SK, Greiner G, Jandt E, Reichardt S, Gührs KH, Stauber RH, Böhmer FD and Heinzel T: A phosphorylation-acetylation switch regulates STAT1 signaling. Genes Dev. 23:223–235. 2009.PubMed/NCBI View Article : Google Scholar
34	Ginter T, Bier C, Knauer SK, Sughra K, Hildebrand D, Münz T, Liebe T, Heller R, Henke A, Stauber RH, et al: Histone deacetylase inhibitors block IFNγ-induced STAT1 phosphorylation. Cell Signal. 24:1453–1460. 2012.PubMed/NCBI View Article : Google Scholar
35	Gu L, Dagvadorj A, Lutz J, Leiby B, Bonuccelli G, Lisanti MP, Addya S, Fortina P, Dasgupta A, Hyslop T, et al: Transcription factor stat3 stimulates metastatic behavior of human prostate cancer cells in vivo, whereas stat5b has a preferential role in the promotion of prostate cancer cell viability and tumor growth. Am J Pathol. 176:1959–1972. 2010.PubMed/NCBI View Article : Google Scholar
36	Huynh J, Etemadi N, Hollande F, Ernst M and Buchert M: The JAK/STAT3 axis: A comprehensive drug target for solid malignancies. Semin Cancer Biol. 45:13–22. 2017.PubMed/NCBI View Article : Google Scholar
37	Johnson DE, O'Keefe RA and Grandis JR: Targeting the IL-6/JAK/STAT3 signalling axis in cancer. Nat Rev Clin Oncol. 15:234–248. 2018.PubMed/NCBI View Article : Google Scholar