Regulation of interferon signaling and HCV‑RNA replication by extracellular matrix

Kuwashiro,Takuya; Iwane,Shinji; Jinghe,Xia; Matsuhashi,Sachiko; Eguchi,Yuichiro; Anzai,Keizo; Fujimoto,Kazuma; Mizuta,Toshihiko; Sakamoto,Naoya; Ikeda,Masanori; Kato,Nobuyuki; Ozaki,Iwata

doi:10.3892/ijmm.2018.3693

Regulation of interferon signaling and HCV‑RNA replication by extracellular matrix

Authors:
- Takuya Kuwashiro
- Shinji Iwane
- Xia Jinghe
- Sachiko Matsuhashi
- Yuichiro Eguchi
- Keizo Anzai
- Kazuma Fujimoto
- Toshihiko Mizuta
- Naoya Sakamoto
- Masanori Ikeda
- Nobuyuki Kato
- Iwata Ozaki
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Affiliations: Department of Internal Medicine, Saga Medical School, Saga University, Saga 849‑8501, Japan, Department of Gastroenterology and Hepatology, Hokkaido University Graduate School of Medicine, Department of Gastroenterology and Hepatology, Graduate School of Medicine, Hokkaido University, Sapporo, Hokkaido 060‑8638, Japan, Department of Tumor Virology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama 700‑8558, Japan
Published online on: May 18, 2018 https://doi.org/10.3892/ijmm.2018.3693
Pages: 957-965
Copyright: © Kuwashiro et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Although interferon (IFN)‑based treatment of patients with chronic hepatitis C virus (HCV) infection is widely applied, treatment resistance is often observed in patients with advanced liver fibrosis. Given that the molecular mechanisms of IFN resistance in liver fibrosis remain elusive, the present study investigated the effects of extracellular matrix (ECM) on IFN signaling in hepatic cells. The native HuH‑7 human hepatoma cell line and HuH‑7 cells were stably transfected with full‑length HCV‑RNA fused with Renilla luciferase (OR6 cells) were cultured on ECM‑coated dishes or non‑coated plastic dishes (NDs), and treated with human IFN‑α. In Huh‑7 cells cultured on coated dishes, the IFN‑stimulated response element (ISRE) luciferase activity was measured following ISRE plasmid transfection and the expression of IFN‑stimulated genes (ISG) were significantly lower than those in cells cultured on NDs. In addition, after IFN‑α treatment, the amount of HCV‑RNA and viral protein produced by OR6 cells cultured on coated dishes was higher than that produced by cells cultured on NDs. When cells were treated with β1‑integrin‑blocking antibody to disrupt the cell‑matrix interaction, the ISRE luciferase activity was restored, and the protein expression of ISG was increased, while that of HCV proteins was suppressed. Treatment of cells with integrin‑linked kinase (ILK) inhibitor or focal adhesion kinase (FAK) inhibitor restored the ISRE luciferase activity and expression of ISG proteins. These results suggested that β1‑integrin‑mediated signals affected the IFN signaling and promoted HCV replication. Therefore, the accumulation of ECM in liver fibrosis may impair IFN signaling through β1‑integrin‑mediated signaling involving ILK and FAK.

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1	Gale M Jr and Foy EM: Evasion of intracellular host defense by hepatitis C virus. Nature. 436:939–945. 2005. View Article : Google Scholar : PubMed/NCBI
2	Borden EC, Sen GC, Uze G, Silverman RH, Ransohoff RM, Foster GR and Stark G: Interferons at age 50: Past, current and future impact on biomedicine. Nat Rev Drug Discov. 6:975–990. 2007. View Article : Google Scholar : PubMed/NCBI
3	Weber F: Interaction of hepatitis C virus with type I interferon system. World J Gastroenterol. 13:4818–4823. 2007. View Article : Google Scholar : PubMed/NCBI
4	Fried MW, Shiffman ML, Reddy KR, Smith C, Marinos G, Gonçales FL Jr, Häussinger D, Diago M, Carosi G, Dhumeaux D, et al: Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection. N Engl J Med. 347:975–982. 2002. View Article : Google Scholar : PubMed/NCBI
5	Manns MP, McHutchison JG, Gordon SC, Rustgi VK, Shiffman M, Reindollar R, Goodman ZD, Koury K, Ling M and Albrecht JK: Peginterferon alfa-2b plus ribavirin compared with interferon alfa-2b plus ribavirin for initial treatment of chronic hepatitis C: A randomised trial. Lancet. 358:958–965. 2001. View Article : Google Scholar : PubMed/NCBI
6	Marrache F, Consigny Y, Ripault MP, Cazals-Hatem D, Martinot M, Boyer N, Degott C, Valla D and Marcellin P: Safety and efficacy of peginterferon plus ribavirin in patients with chronic hepatitis C and bridging fibrosis or cirrhosis. J Viral Hepat. 12:421–428. 2005. View Article : Google Scholar : PubMed/NCBI
7	Everson GT, Hoefs JC, Seeff LB, Bonkovsky HL, Naishadham D, Schiffman ML, Kahn JA, Lok ASF, Di Bisceglie AM, Lee WM, et al: Impact of disease severity on outcome of antiviral therapy for chronic hepatitis C: Lessons from the HALT-C trial. Hepatology. 44:1675–1684. 2006. View Article : Google Scholar : PubMed/NCBI
8	Bruno S, Shiffman ML, Roberts SK, Gane EJ, Messinger D, Hadziyannis SJ and Marcellin P: Efficacy and safety of peginterferon alfa-2a (40KD) plus ribavirin in hepatitis C patients with advanced fibrosis and cirrhosis. Hepatology. 51:388–397. 2010. View Article : Google Scholar
9	Cheng WS, Roberts SK, McCaughan G, Sievert W, Weltman M, Crawford D, Rawlinson W, Marks PS, Thommes J, Rizkalla B, et al: Low virological response and high relapse rates in hepatitis C genotype 1 patients with advanced fibrosis despite adequate therapeutic dosing. J Hepatol. 53:616–623. 2010. View Article : Google Scholar : PubMed/NCBI
10	Asselah T, Estrabaud E, Bieche I, Lapalus M, De Muynck S, Vidaud M, Saadoun D, Soumelis V and Marcellin P: Hepatitis C: Viral and host factors associated with non-response to pegylated interferon plus ribavirin. Liver Int. 30:1259–1269. 2010. View Article : Google Scholar : PubMed/NCBI
11	Jacobson IM, McHutchison JG, Dusheiko G, Di Bisceglie AM, Reddy KR, Bzowej NH, Marcellin P, Muir AJ, Ferenci P, Flisiak R, et al: Telaprevir for previously untreated chronic hepatitis C virus infection. N Engl J Med. 364:2405–2416. 2011. View Article : Google Scholar : PubMed/NCBI
12	Bruno S, Vierling JM, Esteban R, Nyberg LM, Tanno H, Goodman Z, Poordad F, Bacon B, Gottesdiener K, Pedicone LD, et al: Efficacy and safety of boceprevir plus peginterferon-ribavirin in patients with HCV G1 infection and advanced fibrosis/cirrhosis. J Hepatol. 58:479–487. 2013. View Article : Google Scholar
13	Liang TJ and Ghany MG: Current and future therapies for hepatitis C virus infection. N Engl J Med. 368:1907–1917. 2013. View Article : Google Scholar : PubMed/NCBI
14	Casey LC and Lee WM: Hepatitis C virus therapy update 2013. Curr Opin Gastroenterol. 29:243–249. 2013.PubMed/NCBI
15	Shah N, Pierce T and Kowdley KV: Review of directacting antiviral agents for the treatment of chronic hepatitis C. Expert Opin Investig Drugs. 22:1107–1121. 2013. View Article : Google Scholar : PubMed/NCBI
16	Meissner EG, Wu D, Osinusi A, Bon D, Virtaneva K, Sturdevant D, Porcella S, Wang H, Herrmann E, McHutchison J, et al: Endogenous intrahepatic IFNs and association with IFN-free HCV treatment outcome. J Clin Invest. 124:3352–3363. 2014. View Article : Google Scholar : PubMed/NCBI
17	Friedman SL: Mechanisms of hepatic fibrosis. Gastroenterology. 134:1655–1669. 2008. View Article : Google Scholar : PubMed/NCBI
18	Inagaki Y and Okazaki I: Emerging insights into transforming growth factor beta Smad signal in hepatic fibrogenesis. Gut. 56:284–292. 2007. View Article : Google Scholar : PubMed/NCBI
19	Hynes RO: Integrins: Bidirectional, allosteric signaling machines. Cell. 110:673–687. 2002. View Article : Google Scholar : PubMed/NCBI
20	Hehlgans S, Hasse M and Cordes N: Signalling via integrins: Implications for cell survival and anticancer strategies. Biochem Biophys Acta. 1775:163–180. 2017.
21	Millard M, Odde S and Neamati N: Integrin targeted therapeutics. Thearanostics. 1:154–188. 2011. View Article : Google Scholar
22	Hayashida T: Integrins modulate cellular fibrogenesis at multiple levels; Regulation of TGF-β signaling. Endocr Metab Immune Disord Drug Targets. 10:302–319. 2010. View Article : Google Scholar : PubMed/NCBI
23	Ikeda M, Abe K, Dansako H, Nakamura T, Naka K and Kato N: Efficient replication of a full-length hepatitis C virus genome, strain O, in cell culture, and development of a luciferase reporter system. Biochem Biophys Res Commun. 329:1350–1359. 2005. View Article : Google Scholar : PubMed/NCBI
24	Ozaki I, Zhang H, Mizuta T, Ide Y, Eguchi Y, Yasutake T, Sakamaki T, Pestell RG and Yamamoto K: Menatetrenone, a vitamin K2 analogue, inhibits hepatocellular carcinoma cell growth by suppressing cyclin D1 expression through inhibition of nuclear factor kappaB activation. Clin Cancer Res. 13:2236–2245. 2007. View Article : Google Scholar : PubMed/NCBI
25	Wang B, Trippler M, Pei R, Lu M, Broering R, Gerken G and Schlaak JF: Toll-like receptor activated human and murine hepatic stellate cells are potent regulators of hepatitis C virus replication. J Hepatol. 51:1037–1045. 2009. View Article : Google Scholar : PubMed/NCBI
26	Wang Y, Li J, Wang X, Ye L, Zhou Y and Ho W: Induction of interferon-λ contributes to Toll-like receptor-3-activated hepatic stellate cell-mediated hepatitis C virus inhibition in hepatocytes. J Viral Hepat. 20:385–394. 2013. View Article : Google Scholar : PubMed/NCBI
27	Alisi A, Arciello M, Petrini S, Conti B, Missale G and Balsano C: Focal adhesion kinase (FAK) mediates the induction of pro-oncogenic and fibrogenic phenotypes in hepatitis C virus (HCV)-infected cells. PLoS One. 7:e441472012. View Article : Google Scholar : PubMed/NCBI
28	Zhu X and Assoian RK: Integrin-dependent activation of MAP kinase: A link to shape-dependent cell proliferation. Mol Biol Cell. 6:273–282. 1995. View Article : Google Scholar : PubMed/NCBI
29	Khwaja A, Rodriguez-Viciana P, Wennström S, Warne PH and Downward J: Matrix adhesion and Ras transformation both activate a phosphoinositide 3-OH-kinase and protein kinase B/Akt cellular survival pathway. EMBO J. 16:2783–2793. 1997. View Article : Google Scholar : PubMed/NCBI
30	Zhang H, Ozaki I, Mizuta T, Yoshimura T, Matsuhashi S, Eguchi Y, Yasutake T, Hisatomi A, Sakai T and Yamamoto K: Transforming growth factor-beta 1-induced apoptosis is blocked by beta 1-integrin-mediated mitogen-activated protein kinase activation in human hepatoma cells. Cancer Sci. 95:878–886. 2004. View Article : Google Scholar : PubMed/NCBI
31	Yau CY, Wheeler JJ, Sutton KL and Hedley DW: Inhibition of integrin-linked kinase by a selective small molecule inhibitor, QLT0254, inhibits the PI3K/PKB/mTOR, Stat3, and FKHR pathways and tumor growth, and enhances gemcitabine-induced apoptosis in human orthotopic primary pancreatic cancer xenografts. Cancer Res. 65:1497–1504. 2005. View Article : Google Scholar : PubMed/NCBI
32	Riaz A, Ilan N, Vlodavsky I, Li JP and Johansson S: Characterization of heparanase-induced phosphatidylinositol 3-kinase-AKT activation and its integrin dependence. J Biol Chem. 288:12366–12375. 2013. View Article : Google Scholar : PubMed/NCBI
33	Garamszegi N, Garamszegi SP, Samavarchi-Tehrani P, Walford E, Schneiderbauer MM, Wrana JL and Scully SP: Extracellular matrix-induced transforming growth factor-beta receptor signaling dynamics. Oncogene. 29:2368–2380. 2010. View Article : Google Scholar : PubMed/NCBI
34	Ozaki I, Hamajima H, Matsuhashi S and Mizuta T: Regulation of TGF-β1-induced pro-apoptotic signaling by growth factor receptors and extracellular matrix receptor integrins in the liver. Front Physiol. 2:782011. View Article : Google Scholar
35	Shirasaki T, Honda M, Shimakami T, Murai K, Shiomoto T, Okada H, Takabatake A, Tokumaru A, Sakai Y, Yamashita T, et al: Impaired interferon signaling in chronic hepatitis C patients with advanced fibrosis via the transforming growth factor beta signaling pathway. Hepatology. 60:1519–1530. 2014. View Article : Google Scholar : PubMed/NCBI
36	Wang D, Zhou GH, Birkenmeier TM, Gong J, Sun L and Brattain MG: Autocrine transforming growth factor beta-1 modulates the expression of integrin alpha 5 beta1 in human colon carcinoma FET cells. J Biol Chem. 270:14154–14159. 1995. View Article : Google Scholar : PubMed/NCBI
37	Kaur S, Sassano A, Dolniak B, Joshi S, Majchrzak-Kita B, Baker DP, Hay N, Fish EN and Platanias LC: Role of the Akt pathway in mRNA translation of interferon-stimulated genes. Proc Natl Acad Sci USA. 105:4808–4813. 2008. View Article : Google Scholar : PubMed/NCBI
38	Lekmine F, Uddin S, Sassano A, Parmar S, Brachmann SM, Majchrzak B, Sonenberg N, Hay N, Fish EN and Platanias LC: Activation of the p70 S6 kinase and phosphorylation of the 4E-BP1 repressor of mRNA translation by type I interferons. J Biol Chem. 278:27772–27780. 2003. View Article : Google Scholar : PubMed/NCBI
39	Zeller KS, Idevall-Hagren O, Stefansson A, Velling T, Jackson SP, Downward J, Tengholm A and Johansson S: PI3-kinase 110α mediates β1 integrin-induced Akt activation and membrane protrusion during cell attachment and initial spreading. Cell Signal. 22:1838–1848. 2010. View Article : Google Scholar : PubMed/NCBI
40	Tang Q, Zhao S, Wu J, Zheng F, Yang L, Hu J and Hann SS: Inhibition of integrin-linked kinase expression by emodin through crosstalk of AMPKα and ERK1/2 signaling and reciprocal interplay of Sp1 and c-Jun. Cell signaling. 27:1469–1477. 2015. View Article : Google Scholar
41	Hirata E, Girotti MR, Viros A, Hooper S, Spencer-Dene B, Matsuda M, Larkin J, Marais R and Sahai E: Intravital imaging reveals how BRAF inhibition generates drug-tolerant microenvironments with high integrin β1/FAK signaling. Cancer Cell. 27:574–588. 2015. View Article : Google Scholar : PubMed/NCBI
42	Asahina Y, Tsuchiya K, Tamaki N, Hirayama I, Tanaka T, Sato M, Yasui Y, Hosokawa T, Ueda K, Kuzuya T, et al: Effect of aging on risk for hepatocellular carcinoma in chronic hepatitis C virus infection. Hepatology. 52:518–527. 2010. View Article : Google Scholar : PubMed/NCBI
43	Morgan RL, Baack B, Smith BD, Yartel A, Pitasi M and Falck-Ytter Y: Eradication of hepatitis C virus infection and the development of hepatocellular carcinoma: A meta-analysis of observational studies. Ann Intern Med. 158:329–337. 2013. View Article : Google Scholar : PubMed/NCBI
44	Zhang DY and Friedman SL: Fibrosis-dependent mechanisms of hepatocarcinogenesis. Hepatology. 56:769–775. 2012. View Article : Google Scholar : PubMed/NCBI
45	Zitvogel L, Galluzzi L, Kepp O, Smyth MJ and Kroemer G: Type I interferons in anticancer immunity. Nat Rev Immunol. 15:405–414. 2015. View Article : Google Scholar : PubMed/NCBI
46	Yano H, Iemura A, Haramaki M, Ogasawara S, Takayama A, Akiba J and Kojiro M: Interferon alfa receptor expression and growth inhibition by interferon alfa in human liver cancer cell lines. Hepatology. 29:1708–1717. 1999. View Article : Google Scholar : PubMed/NCBI
47	Kusano H, Akiba J, Ogasawara S, Sanada S, Yasumoto M, Nakayama M, Ueda K, Ueda K, Kurita T, Todoroki K, et al: Pegylated interferon-α2a inhibits proliferation of human liver cancer cells in vitro and in vivo. PLoS One. 8:e831952013. View Article : Google Scholar