{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,14]],"date-time":"2026-09-14T14:56:38Z","timestamp":1789397798213,"version":"build-2803163510"},"reference-count":93,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2023,1,30]],"date-time":"2023-01-30T00:00:00Z","timestamp":1675036800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Tokyo Metropolitan Government for drug development targeting liver cirrhosis and the Japan Agency for Medical Research and Development (AMED)"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Hepatitis C virus (HCV) frequently causes chronic infection in the human liver, which may progress to advanced hepatic fibrosis, cirrhosis, and hepatocellular carcinoma. HCV primarily infects highly differentiated quiescent hepatocytes and can modulate cell cycle-regulatory genes and proliferation pathways, which ultimately contribute to persistent infection and pathogenesis. On the other hand, several studies have shown differential regulation of HCV RNA and viral protein expression levels, depending on the proliferation state of hepatocytes and the phase of the cell cycle. HCV typically requires factors provided by host cells for efficient and persistent viral replication. Previously, we found that HCV infection upregulates the expression of ribonucleotide reductase subunit M2 (RRM2) in quiescent hepatocytes. RRM2 is a rate-limiting protein that catalyzes de novo synthesis of deoxyribonucleotide triphosphates, and its expression is highly regulated during various phases of the cell cycle. RRM2 functions as a pro-viral factor essential for HCV RNA synthesis, but its functional role in HCV-induced liver diseases remains unknown. Here, we present a comprehensive review of the role of the hepatocyte cell cycle, in correlation with RRM2 expression, in the regulation of HCV replication. We also discuss the potential relevance of this protein in the pathogenesis of HCV, particularly in the development of hepatocellular carcinoma.<\/jats:p>","DOI":"10.3390\/ijms24032619","type":"journal-article","created":{"date-parts":[[2023,1,30]],"date-time":"2023-01-30T04:58:25Z","timestamp":1675054705000},"page":"2619","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Regulatory Role of Ribonucleotide Reductase Subunit M2 in Hepatocyte Growth and Pathogenesis of Hepatitis C Virus"],"prefix":"10.3390","volume":"24","author":[{"given":"Bouchra","family":"Kitab","sequence":"first","affiliation":[{"name":"Transboundary Animal Disease Center, Joint Faculty of Veterinary Medicine, Kagoshima University, Kagoshima 890-0065, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4403-2018","authenticated-orcid":false,"given":"Kyoko","family":"Tsukiyama-Kohara","sequence":"additional","affiliation":[{"name":"Transboundary Animal Disease Center, Joint Faculty of Veterinary Medicine, Kagoshima University, Kagoshima 890-0065, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,1,30]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"681","DOI":"10.1146\/annurev.biochem.75.103004.142443","article-title":"Ribonucleotide reductases","volume":"75","author":"Nordlund","year":"2006","journal-title":"Annu. Rev. Biochem."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"863","DOI":"10.1002\/j.1460-2075.1984.tb01897.x","article-title":"Localization of ribonucleotide reductase in mammalian cells","volume":"3","author":"Rozell","year":"1984","journal-title":"EMBO J."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"2011","DOI":"10.1038\/onc.2014.155","article-title":"Ribonucleotide reductase and cancer: Biological mechanisms and targeted therapies","volume":"34","author":"Aye","year":"2015","journal-title":"Oncogene"},{"key":"ref_4","unstructured":"Polaris Observatory HCV Collaborators (2022). Global change in hepatitis C virus prevalence and cascade of care between 2015 and 2020: A modelling study. Lancet Gastroenterol. Hepatol., 7, 396\u2013415."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"209","DOI":"10.3322\/caac.21660","article-title":"Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries","volume":"71","author":"Sung","year":"2021","journal-title":"CA Cancer J. Clin."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"727","DOI":"10.1016\/j.jhep.2016.06.015","article-title":"Early occurrence and recurrence of hepatocellular carcinoma in HCV-related cirrhosis treated with direct-acting antivirals","volume":"65","author":"Conti","year":"2016","journal-title":"J. Hepatol."},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Hayes, C.N., Zhang, P., Zhang, Y., and Chayama, K. (2018). Molecular mechanisms of hepatocarcinogenesis following sustained virological response in patients with chronic hepatitis C virus infection. Viruses, 10.","DOI":"10.3390\/v10100531"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"95","DOI":"10.1016\/j.jhep.2016.07.039","article-title":"Reversion of disease manifestations after HCV eradication","volume":"65","author":"Berenguer","year":"2016","journal-title":"J. Hepatol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"2451","DOI":"10.1073\/pnas.88.6.2451","article-title":"Genetic organization and diversity of the hepatitis C virus","volume":"88","author":"Choo","year":"1991","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1476","DOI":"10.1128\/jvi.66.3.1476-1483.1992","article-title":"Internal ribosome entry site within hepatitis C virus RNA","volume":"66","author":"Iizuka","year":"1992","journal-title":"J. Virol."},{"key":"ref_11","first-page":"113","article-title":"Hepatitis C virus proteins: From structure to function","volume":"369","author":"Moradpour","year":"2013","journal-title":"Curr. Top. Microbiol. Immunol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"34122","DOI":"10.1074\/jbc.M000578200","article-title":"Hepatitis C virus core protein enhances p53 function through augmentation of DNA binding affinity and transcriptional ability","volume":"275","author":"Otsuka","year":"2000","journal-title":"J. Biol. Chem."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"427","DOI":"10.1002\/lt.20347","article-title":"Hepatocyte expression of minichromosome maintenance protein-2 predicts fibrosis progression after transplantation for chronic hepatitis C virus: A pilot study","volume":"11","author":"Marshall","year":"2005","journal-title":"Liver Transplant."},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Walters, K.A., Syder, A.J., Lederer, S.L., Diamond, D.L., Paeper, B., Rice, C.M., and Katze, M.G. (2009). Genomic analysis reveals a potential role for cell cycle perturbation in HCV-mediated apoptosis of cultured hepatocytes. PLoS Pathog., 5.","DOI":"10.1371\/journal.ppat.1000269"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"5759","DOI":"10.1074\/jbc.RA118.004397","article-title":"Ribonucleotide reductase M2 promotes RNA replication of hepatitis C virus by protecting NS5B protein from hPLIC1-dependent proteasomal degradation","volume":"294","author":"Kitab","year":"2019","journal-title":"J. Biol. Chem."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"662","DOI":"10.5009\/gnl13392","article-title":"High expression of ribonucleotide reductase subunit M2 correlates with poor prognosis of hepatocellular carcinoma","volume":"8","author":"Lee","year":"2014","journal-title":"Gut Liver"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"2518","DOI":"10.1158\/1078-0432.CCR-09-2214","article-title":"Combined functional genome survey of therapeutic targets for hepatocellular carcinoma","volume":"16","author":"Satow","year":"2010","journal-title":"Clin. Cancer Res."},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Yang, P.M., Lin, L.S., and Liu, T.P. (2020). Sorafenib inhibits Ribonucleotide Reductase Regulatory Subunit M2 (RRM2) in hepatocellular carcinoma cells. Biomolecules, 10.","DOI":"10.3390\/biom10010117"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"316","DOI":"10.1038\/nsmb.2007","article-title":"Structural basis for allosteric regulation of human ribonucleotide reductase by nucleotide-induced oligomerization","volume":"18","author":"Fairman","year":"2011","journal-title":"Nat. Struct. Mol. Biol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"593","DOI":"10.1038\/345593a0","article-title":"Three-dimensional structure of the free radical protein of ribonucleotide reductase","volume":"345","author":"Nordlund","year":"1990","journal-title":"Nature"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"183","DOI":"10.1016\/S1367-5931(03)00025-5","article-title":"Di-iron-tyrosyl radical ribonucleotide reductases","volume":"7","author":"Stubbe","year":"2003","journal-title":"Curr. Opin. Chem. Biol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"11695","DOI":"10.1016\/S0021-9258(20)71265-2","article-title":"Cell cycle-dependent regulation of mammalian ribonucleotide reductase. The S phase-correlated increase in subunit M2 is regulated by de novo protein synthesis","volume":"259","author":"Eriksson","year":"1984","journal-title":"J. Biol. Chem."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"5452","DOI":"10.1021\/bi00475a007","article-title":"S-phase-specific expression of mammalian ribonucleotide reductase R1 and R2 subunit mRNAs","volume":"29","author":"Skog","year":"1990","journal-title":"Biochemistry"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"25239","DOI":"10.1074\/jbc.270.42.25239","article-title":"Role of a proximal NF-Y binding promoter element in S phase-specific expression of mouse ribonucleotide reductase R2 gene","volume":"270","author":"Filatov","year":"1995","journal-title":"J. Biol. Chem."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"10796","DOI":"10.1074\/jbc.M312482200","article-title":"S phase-specific transcription of the mouse ribonucleotide reductase R2 gene requires both a proximal repressive E2F-binding site and an upstream promoter activating region","volume":"279","author":"Chabes","year":"2004","journal-title":"J. Biol. Chem."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1023","DOI":"10.1016\/j.cell.2012.03.043","article-title":"Cyclin F-mediated degradation of ribonucleotide reductase M2 controls genome integrity and DNA repair","volume":"149","author":"Donato","year":"2012","journal-title":"Cell"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"9114","DOI":"10.1016\/S0021-9258(17)39337-7","article-title":"Cell cycle-dependent expression of mammalian ribonucleotide reductase. Differential regulation of the two subunits","volume":"260","author":"Eriksson","year":"1985","journal-title":"J. Biol. Chem."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"17747","DOI":"10.1074\/jbc.M000799200","article-title":"Controlled protein degradation regulates ribonucleotide reductase activity in proliferating mammalian cells during the normal cell cycle and in response to DNA damage and replication blocks","volume":"275","author":"Chabes","year":"2000","journal-title":"J. Biol. Chem."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"3925","DOI":"10.1073\/pnas.0330774100","article-title":"Mouse ribonucleotide reductase R2 protein: A new target for anaphase-promoting complex-Cdh1-mediated proteolysis","volume":"100","author":"Chabes","year":"2003","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"42","DOI":"10.1038\/35003506","article-title":"A ribonucleotide reductase gene involved in a p53-dependent cell-cycle checkpoint for DNA damage","volume":"404","author":"Tanaka","year":"2000","journal-title":"Nature"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"40647","DOI":"10.1074\/jbc.M106088200","article-title":"Mammalian p53R2 protein forms an active ribonucleotide reductase in vitro with the R1 protein, which is expressed both in resting cells in response to DNA damage and in proliferating cells","volume":"276","author":"Guittet","year":"2001","journal-title":"J. Biol. Chem."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"13302","DOI":"10.1073\/pnas.1211289109","article-title":"Mammalian ribonucleotide reductase subunit p53R2 is required for mitochondrial DNA replication and DNA repair in quiescent cells","volume":"109","author":"Pontarin","year":"2012","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1615","DOI":"10.1002\/j.1460-2075.1988.tb02987.x","article-title":"Immunocytochemical evidence for the cytoplasmic localization and differential expression during the cell cycle of the M1 and M2 subunits of mammalian ribonucleotide reductase","volume":"7","author":"Rozell","year":"1988","journal-title":"EMBO J."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"17801","DOI":"10.1073\/pnas.0808198105","article-title":"Ribonucleotide reduction is a cytosolic process in mammalian cells independently of DNA damage","volume":"105","author":"Pontarin","year":"2008","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"333","DOI":"10.1101\/gad.1863810","article-title":"Essential role of Tip60-dependent recruitment of ribonucleotide reductase at DNA damage sites in DNA repair during G1 phase","volume":"24","author":"Niida","year":"2010","journal-title":"Genes Dev."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"60","DOI":"10.1126\/science.276.5309.60","article-title":"Liver regeneration","volume":"276","author":"Michalopoulos","year":"1997","journal-title":"Science"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"10253","DOI":"10.1128\/JVI.01059-06","article-title":"Production of infectious hepatitis C virus by well-differentiated, growth-arrested human hepatoma-derived cells","volume":"80","author":"Sainz","year":"2006","journal-title":"J. Virol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"429","DOI":"10.1053\/j.gastro.2012.04.018","article-title":"Persistence of HCV in quiescent hepatic cells under conditions of an interferon-induced antiviral response","volume":"143","author":"Bauhofer","year":"2012","journal-title":"Gastroenterology"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1252","DOI":"10.1128\/JVI.75.3.1252-1264.2001","article-title":"Characterization of cell lines carrying self-replicating hepatitis C virus RNAs","volume":"75","author":"Pietschmann","year":"2001","journal-title":"J. Virol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"13778","DOI":"10.1128\/JVI.79.21.13778-13793.2005","article-title":"Dissecting the interferon-induced inhibition of hepatitis C virus replication by using a novel host cell line","volume":"79","author":"Windisch","year":"2005","journal-title":"J. Virol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"1181","DOI":"10.1128\/JVI.80.3.1181-1190.2006","article-title":"Effect of cell growth on hepatitis C virus (HCV) replication and a mechanism of cell confluence-based inhibition of HCV RNA and protein expression","volume":"80","author":"Nelson","year":"2006","journal-title":"J. Virol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"152","DOI":"10.1016\/S0016-5085(00)70424-0","article-title":"Cell cycle regulation of hepatitis C virus internal ribosomal entry site-directed translation","volume":"118","author":"Honda","year":"2000","journal-title":"Gastroenterology"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"1513","DOI":"10.1128\/JVI.78.3.1513-1524.2004","article-title":"Virus-host cell interactions during hepatitis C virus RNA replication: Impact of polyprotein expression on the cellular transcriptome and cell cycle association with viral RNA synthesis","volume":"78","author":"Scholle","year":"2004","journal-title":"J. Virol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"10689","DOI":"10.1128\/JVI.77.19.10689-10694.2003","article-title":"Dynamics of subgenomic hepatitis C virus replicon RNA levels in Huh-7 cells after exposure to nucleoside antimetabolites","volume":"77","author":"Stuyver","year":"2003","journal-title":"J. Virol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"1351","DOI":"10.1053\/jhep.2000.7985","article-title":"Hepatitis C virus core protein induces apoptosis and impairs cell-cycle regulation in stably transformed Chinese hamster ovary cells","volume":"31","author":"Honda","year":"2000","journal-title":"Hepatology"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"18159","DOI":"10.1073\/pnas.0505605102","article-title":"Down-regulation of the retinoblastoma tumor suppressor by the hepatitis C virus NS5B RNA-dependent RNA polymerase","volume":"102","author":"Munakata","year":"2005","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"1335","DOI":"10.1371\/journal.ppat.0030139","article-title":"Hepatitis C virus induces E6AP-dependent degradation of the retinoblastoma protein","volume":"3","author":"Munakata","year":"2007","journal-title":"PLoS Pathog."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"684","DOI":"10.1016\/S0955-0674(02)00388-5","article-title":"A revised picture of the E2F transcriptional network and RB function","volume":"14","author":"Stevaux","year":"2002","journal-title":"Curr. Opin. Cell Biol."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"14531","DOI":"10.1074\/jbc.M312822200","article-title":"Activation of the CKI-CDK-Rb-E2F pathway in full genome hepatitis C virus-expressing cells","volume":"279","author":"Tone","year":"2004","journal-title":"J. Biol. Chem."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"26603","DOI":"10.1074\/jbc.M111.225672","article-title":"Hepatitis C virus NS5B protein delays S phase progression in human hepatocyte-derived cells by relocalizing cyclin-dependent kinase 2-interacting protein (CINP)","volume":"286","author":"Wang","year":"2011","journal-title":"J. Biol. Chem."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"4129","DOI":"10.1128\/MCB.21.13.4129-4139.2001","article-title":"ATR-mediated checkpoint pathways regulate phosphorylation and activation of human Chk1","volume":"21","author":"Zhao","year":"2001","journal-title":"Mol. Cell. Biol."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"21767","DOI":"10.1074\/jbc.M300229200","article-title":"Chk1 mediates S and G2 arrests through Cdc25A degradation in response to DNA-damaging agents","volume":"278","author":"Xiao","year":"2003","journal-title":"J. Biol. Chem."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"1542","DOI":"10.1126\/science.1083430","article-title":"Sensing DNA damage through ATRIP recognition of RPA-ssDNA complexes","volume":"300","author":"Zou","year":"2003","journal-title":"Science"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"1428","DOI":"10.4161\/cc.4.10.2055","article-title":"Inhibition of the ATR\/Chk1 pathway induces a p38-dependent S-phase delay in mouse embryonic stem cells","volume":"10","author":"Jirmanova","year":"2005","journal-title":"Cell Cycle"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"221","DOI":"10.1016\/j.cell.2007.12.013","article-title":"Chk1 is a histone H3 threonine 11 kinase that regulates DNA damage-induced transcriptional repression","volume":"132","author":"Shimada","year":"2008","journal-title":"Cell"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"79","DOI":"10.1016\/j.bbrc.2008.06.112","article-title":"Essential role of Chk1 in S phase progression through regulation of RNR2 expression","volume":"374","author":"Naruyama","year":"2008","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"61","DOI":"10.1007\/s00705-003-0202-x","article-title":"Cell cycle perturbation in a human hepatoblastoma cell line constitutively expressing hepatitis C virus core protein","volume":"149","author":"Ruggieri","year":"2004","journal-title":"Arch. Virol."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"134","DOI":"10.1016\/j.virusres.2006.02.004","article-title":"HCV NS2 protein inhibits cell proliferation and induces cell cycle arrest in the S-phase in mammalian cells through down-regulation of cyclin A expression","volume":"121","author":"Yang","year":"2006","journal-title":"Virus Res."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"1179","DOI":"10.1099\/0022-1317-80-5-1179","article-title":"Hepatitis C virus NS5A protein modulates cell cycle regulatory genes and promotes cell growth","volume":"80","author":"Ghosh","year":"1999","journal-title":"J. Gen. Virol."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"2207","DOI":"10.1158\/1078-0432.CCR-06-2218","article-title":"Potent siRNA inhibitors of ribonucleotide reductase subunit RRM2 reduce cell proliferation in vitro and in vivo","volume":"13","author":"Heidel","year":"2007","journal-title":"Clin. Cancer Res."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"956","DOI":"10.3389\/fonc.2019.00956","article-title":"Integrative analysis reveals across-cancer expression patterns and clinical relevance of ribonucleotide reductase in human cancers","volume":"9","author":"Ding","year":"2019","journal-title":"Front. Oncol."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"374","DOI":"10.3816\/CCC.2007.n.007","article-title":"Ribonucleotide reductase subunits M2 and p53R2 are potential biomarkers for metastasis of colon cancer","volume":"6","author":"Liu","year":"2007","journal-title":"Clin. Color. Cancer"},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"190","DOI":"10.1016\/j.bbrc.2006.12.177","article-title":"RRM2 induces NF-kappaB-dependent MMP-9 activation and enhances cellular invasiveness","volume":"354","author":"Duxbury","year":"2007","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"1710","DOI":"10.1038\/sj.bjc.6604344","article-title":"Ribonucleotide reductase subunits M1 and M2 mRNA expression levels and clinical outcome of lung adenocarcinoma patients treated with docetaxel\/gemcitabine","volume":"98","author":"Souglakos","year":"2008","journal-title":"Br. J. Cancer"},{"key":"ref_65","first-page":"1650","article-title":"The mammalian ribonucleotide reductase R2 component cooperates with a variety of oncogenes in mechanisms of cellular transformation","volume":"58","author":"Fan","year":"1998","journal-title":"Cancer Res."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"659","DOI":"10.1097\/IGC.0b013e318287e2b3","article-title":"Small interfering RNA (siRNA)-mediated silencing of the M2 subunit of ribonucleotide reductase: A novel therapeutic strategy in ovarian cancer","volume":"23","author":"Zhang","year":"2013","journal-title":"Int. J. Gynecol. Cancer"},{"key":"ref_67","first-page":"3719","article-title":"Downregulation of ribonucleotide reductase subunits M2 induces apoptosis and G1 arrest of cervical cancer cells","volume":"15","author":"Wang","year":"2018","journal-title":"Oncol. Lett."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"10084","DOI":"10.1016\/j.biomaterials.2013.08.088","article-title":"Inhibition of hepatocellular carcinoma growth using immunoliposomes for co-delivery of adriamycin and ribonucleotide reductase M2 siRNA","volume":"34","author":"Gao","year":"2013","journal-title":"Biomaterials"},{"key":"ref_69","first-page":"4038","article-title":"Regulation of gene expression in HBV- and HCV-related hepatocellular carcinoma: Integrated GWRS and GWGS analyses","volume":"7","author":"Zhou","year":"2014","journal-title":"Int. J. Clin. Exp. Med."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"e6938","DOI":"10.1097\/MD.0000000000006938","article-title":"Bioinformatics analysis of key genes and pathways for hepatocellular carcinoma transformed from cirrhosis","volume":"96","author":"He","year":"2017","journal-title":"Medicine"},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"1034","DOI":"10.1038\/bjc.2013.817","article-title":"Increased expression of RRM2 by human papillomavirus E7 oncoprotein promotes angiogenesis in cervical cancer","volume":"110","author":"Wang","year":"2014","journal-title":"Br. J. Cancer"},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"15271","DOI":"10.3390\/ijms131115271","article-title":"Role of oxidative stress in hepatocarcinogenesis induced by hepatitis C virus","volume":"13","year":"2012","journal-title":"Int. J. Mol. Sci."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"230","DOI":"10.1016\/j.canlet.2009.02.003","article-title":"Interaction of hepatitis C virus core protein with Hsp60 triggers the production of reactive oxygen species and enhances TNF-alpha-mediated apoptosis","volume":"279","author":"Kang","year":"2009","journal-title":"Cancer Lett."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"872","DOI":"10.1016\/j.jhep.2008.12.026","article-title":"Hepatitis C virus NS5A and core proteins induce oxidative stress-mediated calcium signalling alterations in hepatocytes","volume":"50","author":"Dionisio","year":"2009","journal-title":"J. Hepatol."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"1065","DOI":"10.1038\/2053","article-title":"The core protein of hepatitis C virus induces hepatocellular carcinoma in transgenic mice","volume":"4","author":"Moriya","year":"1998","journal-title":"Nat. Med."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"36442","DOI":"10.1074\/jbc.M109.043232","article-title":"Hepatitis C virus impairs p53 via persistent overexpression of 3beta-hydroxysterol delta24-reductase","volume":"284","author":"Nishimura","year":"2009","journal-title":"J. Biol. Chem."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"813","DOI":"10.1002\/hep.28357","article-title":"PI3K\/AKT\/mTOR-dependent stabilization of oncogenic far-upstream element binding proteins in hepatocellular carcinoma cells","volume":"63","author":"Samarin","year":"2016","journal-title":"Hepatology"},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"41422","DOI":"10.18632\/oncotarget.17440","article-title":"P53 suppresses ribonucleotide reductase via inhibiting mTORC1","volume":"8","author":"He","year":"2017","journal-title":"Oncotarget"},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"401","DOI":"10.1016\/j.pan.2022.03.002","article-title":"Ribonucleotide reductase M2 subunit silencing suppresses tumorigenesis in pancreatic cancer via inactivation of PI3K\/AKT\/mTOR pathway","volume":"22","author":"Shan","year":"2022","journal-title":"Pancreatology"},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"2647","DOI":"10.3748\/wjg.v24.i25.2647","article-title":"Role of microRNAs in the main molecular pathways of hepatocellular carcinoma","volume":"24","author":"Vasuri","year":"2018","journal-title":"World J. Gastroenterol."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"1731","DOI":"10.1053\/j.gastro.2019.01.261","article-title":"Biomarkers associated with response to regorafenib in patients with hepatocellular carcinoma","volume":"156","author":"Teufel","year":"2019","journal-title":"Gastroenterology"},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"12876","DOI":"10.1080\/21655979.2022.2078026","article-title":"MicroRNA-582-3p targeting ribonucleotide reductase regulatory subunit M2 inhibits the tumorigenesis of hepatocellular carcinoma by regulating the Wnt\/\u03b2-catenin signaling pathway","volume":"13","author":"Xu","year":"2022","journal-title":"Bioengineered"},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"637","DOI":"10.7326\/M16-2575","article-title":"Oral Direct-Acting Agent Therapy for Hepatitis C Virus Infection: A Systematic Review","volume":"166","author":"Nelson","year":"2017","journal-title":"Ann. Intern. Med."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"1019","DOI":"10.1177\/1060028014534194","article-title":"Sofosbuvir: A Nucleotide NS5B Inhibitor for the Treatment of Chronic Hepatitis C Infection","volume":"48","author":"Rose","year":"2014","journal-title":"Ann. Pharmacother."},{"key":"ref_85","doi-asserted-by":"crossref","unstructured":"Beran, R.K., Sharma, R., Corsa, A.C., Tian, Y., Golde, J., Lundgaard, G., Delaney, W.E., Zhong, W., and Greenstein, A.E. (2012). Cellular growth kinetics distinguish a cyclophilin inhibitor from an HSP90 inhibitor as a selective inhibitor of hepatitis C virus. PLoS ONE, 7.","DOI":"10.1371\/journal.pone.0030286"},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"8507","DOI":"10.1002\/chem.200700260","article-title":"Understanding ribonucleotide reductase inactivation by gemcitabine","volume":"13","author":"Cerqueira","year":"2007","journal-title":"Chemistry"},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"1295","DOI":"10.1080\/17474124.2021.1991792","article-title":"Current epidemiology in hepatocellular carcinoma","volume":"15","author":"Konyn","year":"2021","journal-title":"Expert Rev. Gastroenterol. Hepatol."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"118","DOI":"10.1016\/j.bcp.2016.01.003","article-title":"Inhibition of hepatitis B virus replication by targeting ribonucleotide reductase M2 protein","volume":"103","author":"Liu","year":"2016","journal-title":"Biochem. Pharmacol."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"1551","DOI":"10.7150\/ijbs.44024","article-title":"Circulating tumor DNA as an emerging liquid biopsy biomarker for early diagnosis and therapeutic monitoring in hepatocellular carcinoma","volume":"16","author":"Wu","year":"2020","journal-title":"Int. J. Biol. Sci."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"378","DOI":"10.1056\/NEJMoa0708857","article-title":"Sorafenib in advanced hepatocellular carcinoma","volume":"359","author":"Llovet","year":"2008","journal-title":"N. Engl. J. Med."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"159","DOI":"10.1016\/j.canlet.2013.12.028","article-title":"New biological perspectives for the improvement of the efficacy of sorafenib in hepatocellular carcinoma","volume":"346","author":"Galmiche","year":"2014","journal-title":"Cancer Lett."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"488","DOI":"10.1002\/hep.28574","article-title":"Metallothionein-1G facilitates sorafenib resistance through inhibition of ferroptosis","volume":"64","author":"Sun","year":"2016","journal-title":"Hepatology"},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"799","DOI":"10.1016\/j.chembiol.2021.07.022","article-title":"FADS2-dependent fatty acid desaturation dictates cellular sensitivity to ferroptosis and permissiveness for hepatitis C virus replication","volume":"29","author":"Yamane","year":"2022","journal-title":"Cell Chem. 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