Oxidative Stress Management in Chronic Liver Diseases and Hepatocellular Carcinoma

Daisuke Uchida, Akinobu Takaki, Atsushi Oyama, Takuya Adachi, Nozomu Wada, Hideki Onishi, Hiroyuki Okada, Daisuke Uchida, Akinobu Takaki, Atsushi Oyama, Takuya Adachi, Nozomu Wada, Hideki Onishi, Hiroyuki Okada

Abstract

Chronic viral hepatitis B and C and non-alcoholic fatty liver disease (NAFLD) have been widely acknowledged to be the leading causes of liver cirrhosis and hepatocellular carcinoma. As anti-viral treatment progresses, the impact of NAFLD is increasing. NAFLD can coexist with chronic viral hepatitis and exacerbate its progression. Oxidative stress has been recognized as a chronic liver disease progression-related and cancer-initiating stress response. However, there are still many unresolved issues concerning oxidative stress, such as the correlation between the natural history of the disease and promising treatment protocols. Recent findings indicate that oxidative stress is also an anti-cancer response that is necessary to kill cancer cells. Oxidative stress might therefore be a cancer-initiating response that should be down regulated in the pre-cancerous stage in patients with risk factors for cancer, while it is an anti-cancer cell response that should not be down regulated in the post-cancerous stage, especially in patients using anti-cancer agents. Antioxidant nutrients should be administered carefully according to the patients' disease status. In this review, we will highlight these paradoxical effects of oxidative stress in chronic liver diseases, pre- and post-carcinogenesis.

Keywords: chronic hepatitis; hepatocellular carcinoma; oxidative stress.

Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
A conceptual diagram of probable post-sustained virologic response (SVR) hepatocarcinogenesis in hepatitis C virus (HCV)-related cirrhosis.
Figure 2
Figure 2
A conceptual diagram of oxidative stress in the pre- and post-carcinogenesis stage.

References

    1. Panel A.-I.H.G. Hepatitis C Guidance 2018 Update: AASLD-IDSA Recommendations for Testing, Managing, and Treating Hepatitis C Virus Infection. Clin. Infect. Dis. 2018;67:1477–1492. doi: 10.1093/cid/ciy585.
    1. Nguyen M.H., Wong G., Gane E., Kao J.H., Dusheiko G. Hepatitis B Virus: Advances in Prevention, Diagnosis, and Therapy. Clin. Microbiol. Rev. 2020;33 doi: 10.1128/CMR.00046-19.
    1. Tateishi R., Uchino K., Fujiwara N., Takehara T., Okanoue T., Seike M., Yoshiji H., Yatsuhashi H., Shimizu M., Torimura T., et al. A nationwide survey on non-B, non-C hepatocellular carcinoma in Japan: 2011-2015 update. J. Gastroenterol. 2019;54:367–376. doi: 10.1007/s00535-018-1532-5.
    1. Pacifico L., Anania C., Martino F., Poggiogalle E., Chiarelli F., Arca M., Chiesa C. Management of metabolic syndrome in children and adolescents. Nutr. Metab. Cardiovasc. Dis. 2011;21:455–466. doi: 10.1016/j.numecd.2011.01.011.
    1. Doycheva I., Watt K.D., Alkhouri N. Nonalcoholic fatty liver disease in adolescents and young adults: The next frontier in the epidemic. Hepatology. 2017;65:2100–2109. doi: 10.1002/hep.29068.
    1. Negro F. Natural history of NASH and HCC. Liver Int. 2020;40:72–76. doi: 10.1111/liv.14362.
    1. Eslam M., Newsome P.N., Anstee Q.M., Targher G., Gomez M.R., Zelber-Sagi S., Wong V.W., Dufour J.F., Schattenberg J., Arrese M., et al. A new definition for metabolic associated fatty liver disease: An international expert consensus statement. J. Hepatol. 2020 doi: 10.1016/j.jhep.2020.03.039.
    1. Takaki A., Kawano S., Uchida D., Takahara M., Hiraoka S., Okada H. Paradoxical Roles of Oxidative Stress Response in the Digestive System before and after Carcinogenesis. Cancers. 2019;11:213. doi: 10.3390/cancers11020213.
    1. Luangmonkong T., Suriguga S., Mutsaers H.A.M., Groothuis G.M.M., Olinga P., Boersema M. Targeting Oxidative Stress for the Treatment of Liver Fibrosis. Rev. Physiol. Biochem. Pharmacol. 2018;175:71–102. doi: 10.1007/112_2018_10.
    1. Brand M.D. The sites and topology of mitochondrial superoxide production. Exp. Gerontol. 2010;45:466–472. doi: 10.1016/j.exger.2010.01.003.
    1. Horn A., Jaiswal J.K. Cellular mechanisms and signals that coordinate plasma membrane repair. Cell Mol. Life Sci. CMLS. 2018;75:3751–3770. doi: 10.1007/s00018-018-2888-7.
    1. Demarquoy J., Le Borgne F. Crosstalk between mitochondria and peroxisomes. World J. Biol. Chem. 2015;6:301–309. doi: 10.4331/wjbc.v6.i4.301.
    1. Zeeshan H.M., Lee G.H., Kim H.R., Chae H.J. Endoplasmic Reticulum Stress and Associated ROS. Int. J. Mol. Sci. 2016;17:327. doi: 10.3390/ijms17030327.
    1. Lee J.H., Suh J.H., Choi S.Y., Kang H.J., Lee H.H., Ye B.J., Lee G.R., Jung S.W., Kim C.J., Lee-Kwon W., et al. Tonicity-responsive enhancer-binding protein promotes hepatocellular carcinogenesis, recurrence and metastasis. Gut. 2019;68:347–358. doi: 10.1136/gutjnl-2017-315348.
    1. Pessayre D. Role of mitochondria in non-alcoholic fatty liver disease. J. Gastroenterol. Hepatol. 2007;22(Suppl. 1):S20–S27. doi: 10.1111/j.1440-1746.2006.04640.x.
    1. Nishio T., Hu R., Koyama Y., Liang S., Rosenthal S.B., Yamamoto G., Karin D., Baglieri J., Ma H.Y., Xu J., et al. Activated hepatic stellate cells and portal fibroblasts contribute to cholestatic liver fibrosis in MDR2 knockout mice. J. Hepatol. 2019;71:573–585. doi: 10.1016/j.jhep.2019.04.012.
    1. Poisson J., Lemoinne S., Boulanger C., Durand F., Moreau R., Valla D., Rautou P.E. Liver sinusoidal endothelial cells: Physiology and role in liver diseases. J. Hepatol. 2017;66:212–227. doi: 10.1016/j.jhep.2016.07.009.
    1. Dewidar B., Meyer C., Dooley S., Meindl-Beinker A.N. TGF-beta in Hepatic Stellate Cell Activation and Liver Fibrogenesis-Updated 2019. Cells. 2019;8:1419. doi: 10.3390/cells8111419.
    1. Kawada N., Kristensen D.B., Asahina K., Nakatani K., Minamiyama Y., Seki S., Yoshizato K. Characterization of a stellate cell activation-associated protein (STAP) with peroxidase activity found in rat hepatic stellate cells. J. Biol. Chem. 2001;276:25318–25323. doi: 10.1074/jbc.M102630200.
    1. Thuy le T.T., Matsumoto Y., Thuy T.T., Hai H., Suoh M., Urahara Y., Motoyama H., Fujii H., Tamori A., Kubo S., et al. Cytoglobin deficiency promotes liver cancer development from hepatosteatosis through activation of the oxidative stress pathway. Am. J. Pathol. 2015;185:1045–1060. doi: 10.1016/j.ajpath.2014.12.017.
    1. Thi Thanh Hai N., Thuy L.T.T., Shiota A., Kadono C., Daikoku A., Hoang D.V., Dat N.Q., Sato-Matsubara M., Yoshizato K., Kawada N. Selective overexpression of cytoglobin in stellate cells attenuates thioacetamide-induced liver fibrosis in mice. Sci. Rep. 2018;8:17860. doi: 10.1038/s41598-018-36215-4.
    1. Okina Y., Sato-Matsubara M., Matsubara T., Daikoku A., Longato L., Rombouts K., Thanh Thuy L.T., Ichikawa H., Minamiyama Y., Kadota M., et al. TGF-beta-driven reduction of cytoglobin leads to oxidative DNA damage in stellate cells during non-alcoholic steatohepatitis. J. Hepatol. 2020 doi: 10.1016/j.jhep.2020.03.051.
    1. Gardi C., Arezzini B., Fortino V., Comporti M. Effect of free iron on collagen synthesis, cell proliferation and MMP-2 expression in rat hepatic stellate cells. Biochem. Pharmacol. 2002;64:1139–1145. doi: 10.1016/S0006-2952(02)01257-1.
    1. He G., Karin M. NF-kappaB and STAT3-key players in liver inflammation and cancer. Cell Res. 2011;21:159–168. doi: 10.1038/cr.2010.183.
    1. Robertson C.L., Mendoza R.G., Jariwala N., Dozmorov M., Mukhopadhyay N.D., Subler M.A., Windle J.J., Lai Z., Fisher P.B., Ghosh S., et al. Astrocyte Elevated Gene-1 Regulates Macrophage Activation in Hepatocellular Carcinogenesis. Cancer Res. 2018;78:6436–6446. doi: 10.1158/0008-5472.CAN-18-0659.
    1. Hammoutene A., Rautou P.E. Role of liver sinusoidal endothelial cells in non-alcoholic fatty liver disease. J. Hepatol. 2019;70:1278–1291. doi: 10.1016/j.jhep.2019.02.012.
    1. Muriel P. Role of free radicals in liver diseases. Hepatol. Int. 2009;3:526–536. doi: 10.1007/s12072-009-9158-6.
    1. Yongvanit P., Pinlaor S., Bartsch H. Oxidative and nitrative DNA damage: Key events in opisthorchiasis-induced carcinogenesis. Parasitol. Int. 2012;61:130–135. doi: 10.1016/j.parint.2011.06.011.
    1. Bjelakovic G., Nikolova D., Simonetti R.G., Gluud C. Antioxidant supplements for prevention of gastrointestinal cancers: A systematic review and meta-analysis. Lancet. 2004;364:1219–1228. doi: 10.1016/S0140-6736(04)17138-9.
    1. Uchida D., Takaki A., Ishikawa H., Tomono Y., Kato H., Tsutsumi K., Tamaki N., Maruyama T., Tomofuji T., Tsuzaki R., et al. Oxidative stress balance is dysregulated and represents an additional target for treating cholangiocarcinoma. Free Rad. Res. 2016:1–12. doi: 10.3109/10715762.2016.1172071.
    1. Kuang Y., Sechi M., Nurra S., Ljungman M., Neamati N. Design and Synthesis of Novel Reactive Oxygen Species Inducers for the Treatment of Pancreatic Ductal Adenocarcinoma. J. Med. Chem. 2018;61:1576–1594. doi: 10.1021/acs.jmedchem.7b01463.
    1. Matteoni C.A., Younossi Z.M., Gramlich T., Boparai N., Liu Y.C., McCullough A.J. Nonalcoholic fatty liver disease: A spectrum of clinical and pathological severity. Gastroenterology. 1999;116:1413–1419. doi: 10.1016/S0016-5085(99)70506-8.
    1. Arzumanyan A., Reis H.M., Feitelson M.A. Pathogenic mechanisms in HBV- and HCV-associated hepatocellular carcinoma. Nat. Rev. Cancer. 2013;13:123–135. doi: 10.1038/nrc3449.
    1. Rehermann B. Chronic infections with hepatotropic viruses: Mechanisms of impairment of cellular immune responses. Semin. Liver Dis. 2007;27:152–160. doi: 10.1055/s-2007-979468.
    1. Jacobson I.M., Lim J.K., Fried M.W. American Gastroenterological Association Institute Clinical Practice Update-Expert Review: Care of Patients Who Have Achieved a Sustained Virologic Response After Antiviral Therapy for Chronic Hepatitis C Infection. Gastroenterology. 2017;152:1578–1587. doi: 10.1053/j.gastro.2017.03.018.
    1. Papatheodoridis G., Dalekos G., Sypsa V., Yurdaydin C., Buti M., Goulis J., Calleja J.L., Chi H., Manolakopoulos S., Mangia G., et al. PAGE-B predicts the risk of developing hepatocellular carcinoma in Caucasians with chronic hepatitis B on 5-year antiviral therapy. J. Hepatol. 2016;64:800–806. doi: 10.1016/j.jhep.2015.11.035.
    1. Kim J.H., Kim Y.D., Lee M., Jun B.G., Kim T.S., Suk K.T., Kang S.H., Kim M.Y., Cheon G.J., Kim D.J., et al. Modified PAGE-B score predicts the risk of hepatocellular carcinoma in Asians with chronic hepatitis B on antiviral therapy. J. Hepatol. 2018;69:1066–1073. doi: 10.1016/j.jhep.2018.07.018.
    1. Lee H.W., Kim S.U., Park J.Y., Kim D.Y., Ahn S.H., Han K.H., Kim B.K. External validation of the modified PAGE-B score in Asian chronic hepatitis B patients receiving antiviral therapy. Liver Int. 2019;39:1624–1630. doi: 10.1111/liv.14129.
    1. Clarke W.T., Miranda J., Neidich E., Hudock R., Peters M.G., Kelly E.M. Metabolic syndrome and liver steatosis occur at lower body mass index in US Asian patients with chronic hepatitis B. J. Viral. Hepat. 2019;26:1164–1169. doi: 10.1111/jvh.13147.
    1. Terrault N.A., Lok A.S.F., McMahon B.J., Chang K.M., Hwang J.P., Jonas M.M., Brown R.S., Jr., Bzowej N.H., Wong J.B. Update on Prevention, Diagnosis, and Treatment of Chronic Hepatitis B: AASLD 2018 Hepatitis B Guidance. Clin. Liver Dis. (Hoboken) 2018;12:33–34. doi: 10.1002/cld.728.
    1. European Association for the Study of the Liver EASL 2017 Clinical Practice Guidelines on the management of hepatitis B virus infection. J. Hepatol. 2017;67:370–398. doi: 10.1016/j.jhep.2017.03.021.
    1. Lee H.W., Park S.Y., Lee M., Lee E.J., Lee J., Kim S.U., Park J.Y., Kim D.Y., Ahn S.H., Kim B.K. An optimized hepatocellular carcinoma prediction model for chronic hepatitis B with well-controlled viremia. Liver Int. 2020:10.1111/liv.14451. doi: 10.1111/liv.14451.
    1. Wang K., Lu X., Zhou H., Gao Y., Zheng J., Tong M., Wu C., Liu C., Huang L., Jiang T., et al. Deep learning Radiomics of shear wave elastography significantly improved diagnostic performance for assessing liver fibrosis in chronic hepatitis B: A prospective multicentre study. Gut. 2019;68:729–741. doi: 10.1136/gutjnl-2018-316204.
    1. Cancer Genome Atlas Research Network Electronic address, w.b.e.; Cancer Genome Atlas Research, N. Comprehensive and Integrative Genomic Characterization of Hepatocellular Carcinoma. Cell. 2017;169:1327–1341. doi: 10.1016/j.cell.2017.05.046.
    1. Schulze K., Imbeaud S., Letouze E., Alexandrov L.B., Calderaro J., Rebouissou S., Couchy G., Meiller C., Shinde J., Soysouvanh F., et al. Exome sequencing of hepatocellular carcinomas identifies new mutational signatures and potential therapeutic targets. Nat. Genet. 2015;47:505–511. doi: 10.1038/ng.3252.
    1. Ehedego H., Mohs A., Jansen B., Hiththetiya K., Sicinski P., Liedtke C., Trautwein C. Loss of Cyclin E1 attenuates hepatitis and hepatocarcinogenesis in a mouse model of chronic liver injury. Oncogene. 2018;37:3329–3339. doi: 10.1038/s41388-018-0181-8.
    1. Zhao L.H., Liu X., Yan H.X., Li W.Y., Zeng X., Yang Y., Zhao J., Liu S.P., Zhuang X.H., Lin C., et al. Genomic and oncogenic preference of HBV integration in hepatocellular carcinoma. Nat. Commun. 2016;7:12992. doi: 10.1038/ncomms12992.
    1. Gao Q., Zhu H., Dong L., Shi W., Chen R., Song Z., Huang C., Li J., Dong X., Zhou Y., et al. Integrated Proteogenomic Characterization of HBV-Related Hepatocellular Carcinoma. Cell. 2019;179:561–577. doi: 10.1016/j.cell.2019.08.052.
    1. Liu Y., Tao S., Liao L., Li Y., Li H., Li Z., Lin L., Wan X., Yang X., Chen L. TRIM25 promotes the cell survival and growth of hepatocellular carcinoma through targeting Keap1-Nrf2 pathway. Nat. Commun. 2020;11:348. doi: 10.1038/s41467-019-14190-2.
    1. Takaki A., Yamamoto K. Control of oxidative stress in hepatocellular carcinoma: Helpful or harmful? World J. Hepatol. 2015;7:968–979. doi: 10.4254/wjh.v7.i7.968.
    1. Jung S.Y., Kim Y.J. C-terminal region of HBx is crucial for mitochondrial DNA damage. Cancer Lett. 2013;331:76–83. doi: 10.1016/j.canlet.2012.12.004.
    1. Rahmani Z., Huh K.W., Lasher R., Siddiqui A. Hepatitis B virus X protein colocalizes to mitochondria with a human voltage-dependent anion channel, HVDAC3, and alters its transmembrane potential. J. Virol. 2000;74:2840–2846. doi: 10.1128/JVI.74.6.2840-2846.2000.
    1. Villani R., Monami M., Di Cosimo F., Fioravanti G., Mannucci E., Vendemiale G., Serviddio G. Direct-acting antivirals for HCV treatment in older patients: A systematic review and meta-analysis. J. Viral. Hep. 2019;26:1249–1256. doi: 10.1111/jvh.13169.
    1. Kanwal F., Kramer J., Asch S.M., Chayanupatkul M., Cao Y., El-Serag H.B. Risk of Hepatocellular Cancer in HCV Patients Treated With Direct-Acting Antiviral Agents. Gastroenterology. 2017;153:996–1005. doi: 10.1053/j.gastro.2017.06.012.
    1. Nahon P., Layese R., Bourcier V., Cagnot C., Marcellin P., Guyader D., Pol S., Larrey D., De Ledinghen V., Ouzan D., et al. Incidence of Hepatocellular Carcinoma After Direct Antiviral Therapy for HCV in Patients With Cirrhosis Included in Surveillance Programs. Gastroenterology. 2018;155:1436–1450. doi: 10.1053/j.gastro.2018.07.015.
    1. Singal A.G., Lim J.K., Kanwal F. AGA Clinical Practice Update on Interaction Between Oral Direct-Acting Antivirals for Chronic Hepatitis C Infection and Hepatocellular Carcinoma: Expert Review. Gastroenterology. 2019;156:2149–2157. doi: 10.1053/j.gastro.2019.02.046.
    1. Romano A., Angeli P., Piovesan S., Noventa F., Anastassopoulos G., Chemello L., Cavalletto L., Gambato M., Russo F.P., Burra P., et al. Newly diagnosed hepatocellular carcinoma in patients with advanced hepatitis C treated with DAAs: A prospective population study. J. Hepatol. 2018;69:345–352. doi: 10.1016/j.jhep.2018.03.009.
    1. Calvaruso V., Cabibbo G., Cacciola I., Petta S., Madonia S., Bellia A., Tine F., Distefano M., Licata A., Giannitrapani L., et al. Incidence of Hepatocellular Carcinoma in Patients With HCV-Associated Cirrhosis Treated With Direct-Acting Antiviral Agents. Gastroenterology. 2018;155:411–421. doi: 10.1053/j.gastro.2018.04.008.
    1. Sangiovanni A., Alimenti E., Gattai R., Filomia R., Parente E., Valenti L., Marzi L., Pellegatta G., Borgia G., Gambato M., et al. Undefined/non-malignant hepatic nodules are associated with early occurrence of HCC in DAA-treated patients with HCV-related cirrhosis. J. Hepatol. 2020 doi: 10.1016/j.jhep.2020.03.030.
    1. Knop V., Mauss S., Goeser T., Geier A., Zimmermann T., Herzer K., Postel N., Friedrich-Rust M., Hofmann W.P., German Hepatitis C.R. Dynamics of liver stiffness by transient elastography in patients with chronic hepatitis C virus infection receiving direct-acting antiviral therapy-Results from the German Hepatitis C-Registry. J. Viral. Hepat. 2020 doi: 10.1111/jvh.13280.
    1. Martinez-Camprecios J., Bonis Puig S., Pons Delgado M., Salcedo Allende M.T., Minguez Rosique B., Genesca Ferrer J. Transient elastography in DAA era. Relation between post-SVR LSM and histology. J. Viral. Hepat. 2020;27:453–455. doi: 10.1111/jvh.13245.
    1. Ogasawara N., Saitoh S., Akuta N., Sezaki H., Suzuki F., Fujiyama S., Kawamura Y., Hosaka T., Kobayashi M., Suzuki Y., et al. Advantage of liver stiffness measurement before and after direct-acting antiviral therapy to predict hepatocellular carcinoma and exacerbation of esophageal varices in chronic hepatitis C. Hepatol. Res. 2020;50:426–438. doi: 10.1111/hepr.13467.
    1. Liao Z., Chen L., Zhang X., Zhang H., Tan X., Dong K., Lu X., Zhu H., Liu Q., Zhang Z., et al. PTPRepsilon Acts as a Metastatic Promoter in Hepatocellular Carcinoma by Facilitating Recruitment of SMAD3 to TGF-beta Receptor 1. Hepatology. 2020:10.1002/hep.31104. doi: 10.1002/hep.31104.
    1. D’Ambrosio R., Aghemo A., Rumi M.G., Ronchi G., Donato M.F., Paradis V., Colombo M., Bedossa P. A morphometric and immunohistochemical study to assess the benefit of a sustained virological response in hepatitis C virus patients with cirrhosis. Hepatology. 2012;56:532–543. doi: 10.1002/hep.25606.
    1. Iizuka N., Oka M., Yamada-Okabe H., Mori N., Tamesa T., Okada T., Takemoto N., Tangoku A., Hamada K., Nakayama H., et al. Comparison of gene expression profiles between hepatitis B virus- and hepatitis C virus-infected hepatocellular carcinoma by oligonucleotide microarray data on the basis of a supervised learning method. Cancer Res. 2002;62:3939–3944.
    1. Kato N., Yoshida H., Ono-Nita S.K., Kato J., Goto T., Otsuka M., Lan K., Matsushima K., Shiratori Y., Omata M. Activation of intracellular signaling by hepatitis B and C viruses: C-viral core is the most potent signal inducer. Hepatology. 2000;32:405–412. doi: 10.1053/jhep.2000.9198.
    1. Moriya K., Yotsuyanagi H., Shintani Y., Fujie H., Ishibashi K., Matsuura Y., Miyamura T., Koike K. Hepatitis C virus core protein induces hepatic steatosis in transgenic mice. J. Gen. Virol. 1997;78:1527–1531. doi: 10.1099/0022-1317-78-7-1527.
    1. Moriya K., Fujie H., Shintani Y., Yotsuyanagi H., Tsutsumi T., Ishibashi K., Matsuura Y., Kimura S., Miyamura T., Koike K. The core protein of hepatitis C virus induces hepatocellular carcinoma in transgenic mice. Nat. Med. 1998;4:1065–1067. doi: 10.1038/2053.
    1. Korenaga M., Wang T., Li Y., Showalter L.A., Chan T., Sun J., Weinman S.A. Hepatitis C virus core protein inhibits mitochondrial electron transport and increases reactive oxygen species (ROS) production. J. Biol. Chem. 2005;280:37481–37488. doi: 10.1074/jbc.M506412200.
    1. Rebbani K., Tsukiyama-Kohara K. HCV-Induced Oxidative Stress: Battlefield-Winning Strategy. Oxid. Med. Cell Longev. 2016;2016:7425628. doi: 10.1155/2016/7425628.
    1. Hino K., Nishina S., Hara Y. Iron metabolic disorder in chronic hepatitis C: Mechanisms and relevance to hepatocarcinogenesis. J. Gastroenterol. Hepatol. 2013;28(Suppl. 4):93–98. doi: 10.1111/jgh.12243.
    1. Nishina S., Hino K., Korenaga M., Vecchi C., Pietrangelo A., Mizukami Y., Furutani T., Sakai A., Okuda M., Hidaka I., et al. Hepatitis C virus-induced reactive oxygen species raise hepatic iron level in mice by reducing hepcidin transcription. Gastroenterology. 2008;134:226–238. doi: 10.1053/j.gastro.2007.10.011.
    1. Furutani T., Hino K., Okuda M., Gondo T., Nishina S., Kitase A., Korenaga M., Xiao S.Y., Weinman S.A., Lemon S.M., et al. Hepatic iron overload induces hepatocellular carcinoma in transgenic mice expressing the hepatitis C virus polyprotein. Gastroenterology. 2006;130:2087–2098. doi: 10.1053/j.gastro.2006.02.060.
    1. Day C.P., James O.F. Steatohepatitis: A tale of two “hits”? Gastroenterology. 1998;114:842–845. doi: 10.1016/S0016-5085(98)70599-2.
    1. Tilg H., Moschen A.R. Evolution of inflammation in nonalcoholic fatty liver disease: The multiple parallel hits hypothesis. Hepatology. 2010;52:1836–1846. doi: 10.1002/hep.24001.
    1. Takaki A., Kawai D., Yamamoto K. Molecular mechanisms and new treatment strategies for non-alcoholic steatohepatitis (NASH) Int. J. Mol. Sci. 2014;15:7352–7379. doi: 10.3390/ijms15057352.
    1. Toshimitsu K., Matsuura B., Ohkubo I., Niiya T., Furukawa S., Hiasa Y., Kawamura M., Ebihara K., Onji M. Dietary habits and nutrient intake in non-alcoholic steatohepatitis. Nutrition. 2007;23:46–52. doi: 10.1016/j.nut.2006.09.004.
    1. Federico A., Dallio M., Caprio G.G., Gravina A.G., Picascia D., Masarone M., Persico M., Loguercio C. Qualitative and Quantitative Evaluation of Dietary Intake in Patients with Non-Alcoholic Steatohepatitis. Nutrients. 2017;9:1074. doi: 10.3390/nu9101074.
    1. Ke B., Zhao Z., Ye X., Gao Z., Manganiello V., Wu B., Ye J. Inactivation of NF-kappaB p65 (RelA) in Liver Improves Insulin Sensitivity and Inhibits cAMP/PKA Pathway. Diabetes. 2015;64:3355–3362. doi: 10.2337/db15-0242.
    1. Seki E., Brenner D.A., Karin M. A liver full of JNK: Signaling in regulation of cell function and disease pathogenesis, and clinical approaches. Gastroenterology. 2012;143:307–320. doi: 10.1053/j.gastro.2012.06.004.
    1. Gadd V.L., Skoien R., Powell E.E., Fagan K.J., Winterford C., Horsfall L., Irvine K., Clouston A.D. The portal inflammatory infiltrate and ductular reaction in human nonalcoholic fatty liver disease. Hepatology. 2014;59:1393–1405. doi: 10.1002/hep.26937.
    1. Lee W.J., Tateya S., Cheng A.M., Rizzo-DeLeon N., Wang N.F., Handa P., Wilson C.L., Clowes A.W., Sweet I.R., Bomsztyk K., et al. M2 Macrophage Polarization Mediates Anti-inflammatory Effects of Endothelial Nitric Oxide Signaling. Diabetes. 2015;64:2836–2846. doi: 10.2337/db14-1668.
    1. Chettouh H., Lequoy M., Fartoux L., Vigouroux C., Desbois-Mouthon C. Hyperinsulinaemia and insulin signalling in the pathogenesis and the clinical course of hepatocellular carcinoma. Liver Int. 2015;35:2203–2217. doi: 10.1111/liv.12903.
    1. Mao Y.Q., Houry W.A. The Role of Pontin and Reptin in Cellular Physiology and Cancer Etiology. Front. Mol. Biosci. 2017;4:58. doi: 10.3389/fmolb.2017.00058.
    1. Mello T., Materozzi M., Zanieri F., Simeone I., Ceni E., Bereshchenko O., Polvani S., Tarocchi M., Marroncini G., Nerlov C., et al. Liver haploinsufficiency of RuvBL1 causes hepatic insulin resistance and enhances hepatocellular carcinoma progression. Int. J. Cancer. 2020;146:3410–3422. doi: 10.1002/ijc.32787.
    1. Haurie V., Menard L., Nicou A., Touriol C., Metzler P., Fernandez J., Taras D., Lestienne P., Balabaud C., Bioulac-Sage P., et al. Adenosine triphosphatase pontin is overexpressed in hepatocellular carcinoma and coregulated with reptin through a new posttranslational mechanism. Hepatology. 2009;50:1871–1883. doi: 10.1002/hep.23215.
    1. Romeo S., Kozlitina J., Xing C., Pertsemlidis A., Cox D., Pennacchio L.A., Boerwinkle E., Cohen J.C., Hobbs H.H. Genetic variation in PNPLA3 confers susceptibility to nonalcoholic fatty liver disease. Nat. Genet. 2008;40:1461–1465. doi: 10.1038/ng.257.
    1. Sookoian S., Pirola C.J. Meta-analysis of the influence of I148M variant of patatin-like phospholipase domain containing 3 gene (PNPLA3) on the susceptibility and histological severity of nonalcoholic fatty liver disease. Hepatology. 2011;53:1883–1894. doi: 10.1002/hep.24283.
    1. Kozlitina J., Smagris E., Stender S., Nordestgaard B.G., Zhou H.H., Tybjaerg-Hansen A., Vogt T.F., Hobbs H.H., Cohen J.C. Exome-wide association study identifies a TM6SF2 variant that confers susceptibility to nonalcoholic fatty liver disease. Nat. Genet. 2014;46:352–356. doi: 10.1038/ng.2901.
    1. Zhou Y., Llaurado G., Oresic M., Hyotylainen T., Orho-Melander M., Yki-Jarvinen H. Circulating triacylglycerol signatures and insulin sensitivity in NAFLD associated with the E167K variant in TM6SF2. J. Hepatol. 2015;62:657–663. doi: 10.1016/j.jhep.2014.10.010.
    1. Kawaguchi T., Shima T., Mizuno M., Mitsumoto Y., Umemura A., Kanbara Y., Tanaka S., Sumida Y., Yasui K., Takahashi M., et al. Risk estimation model for nonalcoholic fatty liver disease in the Japanese using multiple genetic markers. PLoS ONE. 2018;13:e0185490. doi: 10.1371/journal.pone.0185490.
    1. Kawai D., Takaki A., Nakatsuka A., Wada J., Tamaki N., Yasunaka T., Koike K., Tsuzaki R., Matsumoto K., Miyake Y., et al. Hydrogen-rich water prevents progression of nonalcoholic steatohepatitis and accompanying hepatocarcinogenesis in mice. Hepatology. 2012;56:912–921. doi: 10.1002/hep.25782.
    1. Bugianesi E. Non-alcoholic steatohepatitis and cancer. Clin. Liver Dis. 2007;11:191–207. doi: 10.1016/j.cld.2007.02.006.
    1. Cortez-Pinto H., Chatham J., Chacko V.P., Arnold C., Rashid A., Diehl A.M. Alterations in liver ATP homeostasis in human nonalcoholic steatohepatitis: A pilot study. JAMA. 1999;282:1659–1664. doi: 10.1001/jama.282.17.1659.
    1. Serviddio G., Bellanti F., Tamborra R., Rollo T., Romano A.D., Giudetti A.M., Capitanio N., Petrella A., Vendemiale G., Altomare E. Alterations of hepatic ATP homeostasis and respiratory chain during development of non-alcoholic steatohepatitis in a rodent model. Eur. J. Clin. Invest. 2008;38:245–252. doi: 10.1111/j.1365-2362.2008.01936.x.
    1. Nelson J.E., Wilson L., Brunt E.M., Yeh M.M., Kleiner D.E., Unalp-Arida A., Kowdley K.V. Relationship between the pattern of hepatic iron deposition and histological severity in nonalcoholic fatty liver disease. Hepatology. 2011;53:448–457. doi: 10.1002/hep.24038.
    1. Higuchi T., Moriyama M., Fukushima A., Matsumura H., Matsuoka S., Kanda T., Sugitani M., Tsunemi A., Ueno T., Fukuda N. Association of mRNA expression of iron metabolism-associated genes and progression of non-alcoholic steatohepatitis in rats. Oncotarget. 2018;9:26183–26194. doi: 10.18632/oncotarget.25488.
    1. Siddique A., Nelson J.E., Aouizerat B., Yeh M.M., Kowdley K.V., Network N.C.R. Iron Deficiency in Patients With Nonalcoholic Fatty Liver Disease Is Associated With Obesity, Female Gender, and Low Serum Hepcidin. Clin. Gastroenterol. Hepatol. 2013 doi: 10.1016/j.cgh.2013.11.017.
    1. Peternelj T.T., Coombes J.S. Antioxidant supplementation during exercise training: Beneficial or detrimental? Sports Med. 2011;41:1043–1069. doi: 10.2165/11594400-000000000-00000.
    1. Bellezza I., Mierla A.L., Minelli A. Nrf2 and NF-kappaB and Their Concerted Modulation in Cancer Pathogenesis and Progression. Cancers. 2010;2:483–497. doi: 10.3390/cancers2020483.
    1. Husain H., Latief U., Ahmad R. Pomegranate action in curbing the incidence of liver injury triggered by Diethylnitrosamine by declining oxidative stress via Nrf2 and NFkappaB regulation. Sci. Rep. 2018;8:8606. doi: 10.1038/s41598-018-26611-1.
    1. Czaja A.J. Review article: Iron disturbances in chronic liver diseases other than haemochromatosis-pathogenic, prognostic, and therapeutic implications. Aliment. Pharm. Ther. 2019;49:681–701. doi: 10.1111/apt.15173.
    1. Olechnowicz J., Tinkov A., Skalny A., Suliburska J. Zinc status is associated with inflammation, oxidative stress, lipid, and glucose metabolism. J. Physiol. Sci. 2018;68:19–31. doi: 10.1007/s12576-017-0571-7.
    1. Stamoulis I., Kouraklis G., Theocharis S. Zinc and the liver: An active interaction. Dig. Dis. Sci. 2007;52:1595–1612. doi: 10.1007/s10620-006-9462-0.
    1. Zhong W., Wei X., Hao L., Lin T.D., Yue R., Sun X., Guo W., Dong H., Li T., Ahmadi A.R., et al. Paneth Cell Dysfunction Mediates Alcohol-related Steatohepatitis Through Promoting Bacterial Translocation in Mice: Role of Zinc Deficiency. Hepatology. 2020;71:1575–1591. doi: 10.1002/hep.30945.
    1. Podany A., Rauchut J., Wu T., Kawasawa Y.I., Wright J., Lamendella R., Soybel D.I., Kelleher S.L. Excess Dietary Zinc Intake in Neonatal Mice Causes Oxidative Stress and Alters Intestinal Host-Microbe Interactions. Mol. Nutr. Food Res. 2019;63:e1800947. doi: 10.1002/mnfr.201800947.
    1. Sunde R.A., Raines A.M., Barnes K.M., Evenson J.K. Selenium status highly regulates selenoprotein mRNA levels for only a subset of the selenoproteins in the selenoproteome. Biosci. Rep. 2009;29:329–338. doi: 10.1042/BSR20080146.
    1. Goda K., Muta K., Yasui Y., Oshida S., Kitatani K., Takekoshi S. Selenium and Glutathione-Depleted Rats as a Sensitive Animal Model to Predict Drug-Induced Liver Injury in Humans. Int. J. Mol. Sci. 2019;20:3141. doi: 10.3390/ijms20133141.
    1. Loguercio C., De Girolamo V., Federico A., Feng S.L., Crafa E., Cataldi V., Gialanella G., Moro R., Del Vecchio Blanco C. Relationship of blood trace elements to liver damage, nutritional status, and oxidative stress in chronic nonalcoholic liver disease. Biol. Trace Elem. Res. 2001;81:245–254. doi: 10.1385/BTER:81:3:245.
    1. De Oliveira D.G., de Faria Ghetti F., Moreira A.P.B., Hermsdorff H.H.M., de Oliveira J.M., de Castro Ferreira L. Association between dietary total antioxidant capacity and hepatocellular ballooning in nonalcoholic steatohepatitis: A cross-sectional study. Eur. J. Nutr. 2019;58:2263–2270. doi: 10.1007/s00394-018-1776-0.
    1. Goncalves D., Lima C., Ferreira P., Costa P., Costa A., Figueiredo W., Cesar T. Orange juice as dietary source of antioxidants for patients with hepatitis C under antiviral therapy. Food Nutr. Res. 2017;61:1296675. doi: 10.1080/16546628.2017.1296675.
    1. Ivancovsky-Wajcman D., Fliss-Isakov N., Salomone F., Webb M., Shibolet O., Kariv R., Zelber-Sagi S. Dietary vitamin E and C intake is inversely associated with the severity of nonalcoholic fatty liver disease. Dig. Liver Dis. 2019;51:1698–1705. doi: 10.1016/j.dld.2019.06.005.
    1. Wei J., Lei G.H., Fu L., Zeng C., Yang T., Peng S.F. Association between Dietary Vitamin C Intake and Non-Alcoholic Fatty Liver Disease: A Cross-Sectional Study among Middle-Aged and Older Adults. PLoS ONE. 2016;11:e0147985. doi: 10.1371/journal.pone.0147985.
    1. Kato J., Miyanishi K., Kobune M., Nakamura T., Takada K., Takimoto R., Kawano Y., Takahashi S., Takahashi M., Sato Y., et al. Long-term phlebotomy with low-iron diet therapy lowers risk of development of hepatocellular carcinoma from chronic hepatitis C. J. Gastroenterol. 2007;42:830–836. doi: 10.1007/s00535-007-2095-z.
    1. Diglio D.C., Fernandes S.A., Stein J., Azeredo-da-Silva A., de Mattos A.A., Tovo C.V. Role of zinc supplementation in the management of chronic liver diseases: A systematic review and meta-analysis. Ann. Hepatol. 2020;19:190–196. doi: 10.1016/j.aohep.2019.08.011.
    1. Murakami Y., Koyabu T., Kawashima A., Kakibuchi N., Kawakami T., Takaguchi K., Kita K., Okita M. Zinc supplementation prevents the increase of transaminase in chronic hepatitis C patients during combination therapy with pegylated interferon alpha-2b and ribavirin. J. Nutr. Sci. Vitaminol. 2007;53:213–218. doi: 10.3177/jnsv.53.213.
    1. Takahashi M., Saito H., Higashimoto M., Hibi T. Possible inhibitory effect of oral zinc supplementation on hepatic fibrosis through downregulation of TIMP-1: A pilot study. Hepatol. Res. 2007;37:405–409. doi: 10.1111/j.1872-034X.2007.00065.x.
    1. Kodama H., Tanaka M., Naito Y., Katayama K., Moriyama M. Japan’s Practical Guidelines for Zinc Deficiency with a Particular Focus on Taste Disorders, Inflammatory Bowel Disease, and Liver Cirrhosis. Int. J. Mol. Sci. 2020;21:2941. doi: 10.3390/ijms21082941.
    1. Winther K.H., Papini E., Attanasio R., Negro R., Hegedus L. A 2018 European Thyroid Association Survey on the Use of Selenium Supplementation in Hashimoto’s Thyroiditis. Eur. Thyroid. J. 2020;9:99–105. doi: 10.1159/000504781.
    1. Vieira M.L., Fonseca F.L., Costa L.G., Beltrame R.L., Chaves C.M., Cartum J., Alves S.I., Azzalis L.A., Junqueira V.B., Pereria E.C., et al. Supplementation with selenium can influence nausea, fatigue, physical, renal, and liver function of children and adolescents with cancer. J. Med. Food. 2015;18:109–117. doi: 10.1089/jmf.2014.0030.
    1. Valimaki M., Alfthan G., Vuoristo M., Ylikahri R. Effects of selenium supplementation on blood and urine selenium levels and liver function in patients with primary biliary cirrhosis. Clin. Chim. Acta. 1991;196:7–15. doi: 10.1016/0009-8981(91)90203-O.
    1. Shi Y., Zou Y., Shen Z., Xiong Y., Zhang W., Liu C., Chen S. Trace Elements, PPARs, and Metabolic Syndrome. Int. J. Mol. Sci. 2020;21:2612. doi: 10.3390/ijms21072612.
    1. Vinceti M., Filippini T., Rothman K.J. Selenium exposure and the risk of type 2 diabetes: A systematic review and meta-analysis. Eur. J. Epidemiol. 2018;33:789–810. doi: 10.1007/s10654-018-0422-8.
    1. Taylor P.R., Li B., Dawsey S.M., Li J.Y., Yang C.S., Guo W., Blot W.J. Prevention of esophageal cancer: The nutrition intervention trials in Linxian, China. Linxian Nutrition Intervention Trials Study Group. Cancer Res. 1994;54:2029s–2031s.
    1. Klein E.A., Thompson I.M., Jr., Tangen C.M., Crowley J.J., Lucia M.S., Goodman P.J., Minasian L.M., Ford L.G., Parnes H.L., Gaziano J.M., et al. Vitamin E and the risk of prostate cancer: The Selenium and Vitamin E Cancer Prevention Trial (SELECT) JAMA. 2011;306:1549–1556. doi: 10.1001/jama.2011.1437.
    1. Omenn G.S., Goodman G.E., Thornquist M.D., Balmes J., Cullen M.R., Glass A., Keogh J.P., Meyskens F.L., Jr., Valanis B., Williams J.H., Jr., et al. Risk factors for lung cancer and for intervention effects in CARET, the Beta-Carotene and Retinol Efficacy Trial. J. Natl. Cancer Inst. 1996;88:1550–1559. doi: 10.1093/jnci/88.21.1550.
    1. Al-Busafi S.A., Bhat M., Wong P., Ghali P., Deschenes M. Antioxidant therapy in nonalcoholic steatohepatitis. Hepat. Res. Treat. 2012;2012:947575. doi: 10.1155/2012/947575.
    1. Sanyal A.J., Chalasani N., Kowdley K.V., McCullough A., Diehl A.M., Bass N.M., Neuschwander-Tetri B.A., Lavine J.E., Tonascia J., Unalp A., et al. Pioglitazone, vitamin E, or placebo for nonalcoholic steatohepatitis. N. Engl. J. Med. 2010;362:1675–1685. doi: 10.1056/NEJMoa0907929.
    1. Biondo L.A., Teixeira A.A.S., de Oliveira Santos Ferreira K.C., Neto J.C.R. Pharmacological strategies for insulin sensitivity: Thiazolidinediones and metformin. Curr. Pharm. Des. 2020:10.2174/1381612826666200122124116. doi: 10.2174/1381612826666200122124116.
    1. Rena G., Hardie D.G., Pearson E.R. The mechanisms of action of metformin. Diabetologia. 2017;60:1577–1585. doi: 10.1007/s00125-017-4342-z.
    1. Do M.T., Kim H.G., Khanal T., Choi J.H., Kim D.H., Jeong T.C., Jeong H.G. Metformin inhibits heme oxygenase-1 expression in cancer cells through inactivation of Raf-ERK-Nrf2 signaling and AMPK-independent pathways. Toxicol. Appl. Pharmacol. 2013;271:229–238. doi: 10.1016/j.taap.2013.05.010.
    1. Belfort R., Harrison S.A., Brown K., Darland C., Finch J., Hardies J., Balas B., Gastaldelli A., Tio F., Pulcini J., et al. A placebo-controlled trial of pioglitazone in subjects with nonalcoholic steatohepatitis. N. Engl. J. Med. 2006;355:2297–2307. doi: 10.1056/NEJMoa060326.
    1. Balas B., Belfort R., Harrison S.A., Darland C., Finch J., Schenker S., Gastaldelli A., Cusi K. Pioglitazone treatment increases whole body fat but not total body water in patients with non-alcoholic steatohepatitis. J. Hepatol. 2007;47:565–570. doi: 10.1016/j.jhep.2007.04.013.
    1. Ishikawa H., Takaki A., Tsuzaki R., Yasunaka T., Koike K., Shimomura Y., Seki H., Matsushita H., Miyake Y., Ikeda F., et al. L-carnitine prevents progression of non-alcoholic steatohepatitis in a mouse model with upregulation of mitochondrial pathway. PLoS ONE. 2014;9:e100627. doi: 10.1371/journal.pone.0100627.
    1. Malaguarnera M., Gargante M.P., Russo C., Antic T., Vacante M., Malaguarnera M., Avitabile T., Li Volti G., Galvano F. L-carnitine supplementation to diet: A new tool in treatment of nonalcoholic steatohepatitis--a randomized and controlled clinical trial. Am. J. Gastroenterol. 2010;105:1338–1345. doi: 10.1038/ajg.2009.719.
    1. Liu Y., Wen P.H., Zhang X.X., Dai Y., He Q. Breviscapine ameliorates CCl4induced liver injury in mice through inhibiting inflammatory apoptotic response and ROS generation. Int. J. Mol. Med. 2018;42:755–768. doi: 10.3892/ijmm.2018.3651.
    1. Loguercio C., Festi D. Silybin and the liver: From basic research to clinical practice. World J. Gastroenterol. WJG. 2011;17:2288–2301. doi: 10.3748/wjg.v17.i18.2288.
    1. Salomone F., Barbagallo I., Godos J., Lembo V., Currenti W., Cina D., Avola R., D’Orazio N., Morisco F., Galvano F., et al. Silibinin Restores NAD(+) Levels and Induces the SIRT1/AMPK Pathway in Non-Alcoholic Fatty Liver. Nutrients. 2017;9:1086. doi: 10.3390/nu9101086.
    1. Lama S., Vanacore D., Diano N., Nicolucci C., Errico S., Dallio M., Federico A., Loguercio C., Stiuso P. Ameliorative effect of Silybin on bisphenol A induced oxidative stress, cell proliferation and steroid hormones oxidation in HepG2 cell cultures. Sci. Rep. 2019;9:3228. doi: 10.1038/s41598-019-40105-8.
    1. Wah Kheong C., Nik Mustapha N.R., Mahadeva S. A Randomized Trial of Silymarin for the Treatment of Nonalcoholic Steatohepatitis. Clin. Gastroenterol. Hepatol. 2017;15:1940–1949. doi: 10.1016/j.cgh.2017.04.016.
    1. Hasegawa K., Kokudo N., Makuuchi M., Izumi N., Ichida T., Kudo M., Ku Y., Sakamoto M., Nakashima O., Matsui O., et al. Comparison of resection and ablation for hepatocellular carcinoma: A cohort study based on a Japanese nationwide survey. J. Hepatol. 2013;58:724–729. doi: 10.1016/j.jhep.2012.11.009.
    1. Poon R.T., Fan S.T., Ng I.O., Lo C.M., Liu C.L., Wong J. Different risk factors and prognosis for early and late intrahepatic recurrence after resection of hepatocellular carcinoma. Cancer. 2000;89:500–507. doi: 10.1002/1097-0142(20000801)89:3<500::AID-CNCR4>;2-O.
    1. Yamamoto N., Okano K., Kushida Y., Deguchi A., Yachida S., Suzuki Y. Clinicopathology of recurrent hepatocellular carcinomas after radiofrequency ablation treated with salvage surgery. Hepatol. Res. 2014;44:1062–1071. doi: 10.1111/hepr.12223.
    1. Tanaka S., Mogushi K., Yasen M., Ban D., Noguchi N., Irie T., Kudo A., Nakamura N., Tanaka H., Yamamoto M., et al. Oxidative stress pathways in noncancerous human liver tissue to predict hepatocellular carcinoma recurrence: A prospective, multicenter study. Hepatology. 2011;54:1273–1281. doi: 10.1002/hep.24536.
    1. Shertzer H.G., Clay C.D., Genter M.B., Schneider S.N., Nebert D.W., Dalton T.P. Cyp1a2 protects against reactive oxygen production in mouse liver microsomes. Free Radic. Biol. Med. 2004;36:605–617. doi: 10.1016/j.freeradbiomed.2003.11.013.
    1. Qi X., Ng K.T., Lian Q.Z., Liu X.B., Li C.X., Geng W., Ling C.C., Ma Y.Y., Yeung W.H., Tu W.W., et al. Clinical significance and therapeutic value of glutathione peroxidase 3 (GPx3) in hepatocellular carcinoma. Oncotarget. 2014;5:11103–11120. doi: 10.18632/oncotarget.2549.
    1. Pinter M., Peck-Radosavljevic M. Review article: Systemic treatment of hepatocellular carcinoma. Aliment. Pharmacol. Ther. 2018;48:598–609. doi: 10.1111/apt.14913.
    1. Coriat R., Nicco C., Chereau C., Mir O., Alexandre J., Ropert S., Weill B., Chaussade S., Goldwasser F., Batteux F. Sorafenib-induced hepatocellular carcinoma cell death depends on reactive oxygen species production in vitro and in vivo. Mol. Cancer Ther. 2012;11:2284–2293. doi: 10.1158/1535-7163.MCT-12-0093.
    1. Zheng A., Chevalier N., Calderoni M., Dubuis G., Dormond O., Ziros P.G., Sykiotis G.P., Widmann C. CRISPR/Cas9 genome-wide screening identifies KEAP1 as a sorafenib, lenvatinib, and regorafenib sensitivity gene in hepatocellular carcinoma. Oncotarget. 2019;10:7058–7070. doi: 10.18632/oncotarget.27361.

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