{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,12]],"date-time":"2025-10-12T04:04:09Z","timestamp":1760241849718,"version":"build-2065373602"},"reference-count":48,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2018,9,27]],"date-time":"2018-09-27T00:00:00Z","timestamp":1538006400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100005994","name":"Lietuvos Valstybinis Mokslo ir Studiju Fondas","doi-asserted-by":"publisher","award":["TAP LU-1\/2016"],"award-info":[{"award-number":["TAP LU-1\/2016"]}],"id":[{"id":"10.13039\/501100005994","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Medicina"],"abstract":"<jats:p>Background and objectives: The hepatitis C virus (HCV) is the major causative agent of hepatocellular carcinoma (HCC) in the western world. The efficacy of surveillance programs for early detection of HCC is not satisfactory: many tumors are diagnosed at the late, incurable stages. Therefore, there is a need in reliable prognostic markers for the proper follow-up of HCV-positive patients. The aim of the present study was to assess the prognostic value of the uridine\u2013cytidine kinase-like protein 1 (UCKL-1), a putative oncoprotein, together with genetically determined polymorphisms in the interleukin 28B (IL28B) gene (rs12979860, rs8099917) in the development of HCC in HCV-positive cirrhotic patients. Materials and Methods: We included 32 HCV cirrhotic patients, 21 (65.6%) of whom had HCC. The expression of UCKL-1 was assessed in liver tissue sections, using immunohistochemistry. For IL28B rs12979860 and rs8099917 genotype analysis, the corresponding genomic regions were amplified by polymerase chain reaction (PCR) with appropriate primers. Results: We have found that UCKL-1 expression was significantly increased in HCC (p = 0.003). The presence of rs8099917 TT single-nucleotide polymorphism (SNP) elevated the chances of HCC manifestation more than sevenfold (OR = 7.3, p = 0.0273). The presence of rs12979860 CC SNP also heightened HCC chances more than sevenfold (OR = 7.5, p = 0.0765). Moreover, in the HCC group, a combination of IL28B rs12979860 non-TT and rs8099917 TT genotypes was observed more often, compared with the non-HCC group. Other combinations of IL28B rs12979860 and rs8099917 SNIPs were associated with a reduced risk of HCC development, approximately at the same extent. Conclusions: The presence of IL28B rs8099917 TT and rs12979860 CC SNPs, but not the intensity of UCKL-1 expression, is strongly associated with increased chances of HCC development in HCV-positive cirrhotic patients.<\/jats:p>","DOI":"10.3390\/medicina54050067","type":"journal-article","created":{"date-parts":[[2018,9,28]],"date-time":"2018-09-28T02:54:54Z","timestamp":1538103294000},"page":"67","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Impact of the Uridine\u2013Cytidine Kinase Like-1 Protein and IL28B rs12979860 and rs8099917 SNPs on the Development of Hepatocellular Carcinoma in Cirrhotic Chronic Hepatitis C Patients\u2014A Pilot Study"],"prefix":"10.3390","volume":"54","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4417-4198","authenticated-orcid":false,"given":"Arida","family":"Buivydiene","sequence":"first","affiliation":[{"name":"Center of Hepatology, Gastroenterology and Dietetics, Clinic of Gastroenterology, Nephrourology and Surgery, Vilnius University, LT-08661 Vilnius, Lithuania"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Valentina","family":"Liakina","sequence":"additional","affiliation":[{"name":"Center of Hepatology, Gastroenterology and Dietetics, Clinic of Gastroenterology, Nephrourology and Surgery, Vilnius University, LT-08661 Vilnius, Lithuania"},{"name":"Department of Chemistry and Bioengineering, Faculty of Fundamental Sciences, Vilnius Gediminas Technical University, LT-10223 Vilnius, Lithuania"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7001-4035","authenticated-orcid":false,"given":"Elena","family":"Kashuba","sequence":"additional","affiliation":[{"name":"Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, SE-171 77 Stockholm, Sweden"},{"name":"RE Kavetsky Institute of Experimental Pathology, Oncology and Radiobiology, UA-03022 Kyiv, Ukraine"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jolita","family":"Norkuniene","sequence":"additional","affiliation":[{"name":"Department of Mathematical Statistics, Faculty of Fundamental Sciences, Vilnius Gediminas Technical University, LT-10223 Vilnius, Lithuania"},{"name":"Vilniaus Kolegija\/University of Applied Sciences, LT-08105 Vilnius, Lithuania"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Skirmante","family":"Jokubauskiene","sequence":"additional","affiliation":[{"name":"Department of Pathology, Forensic Medicine and Pharmacology, Faculty of Medicine, Vilnius University, LT-03101 Vilnius, Lithuanian, <email>skirmante.jokubauskiene@mf.vu.lt<\/email>"},{"name":"National Center of Pathology, LT-08406 Vilnius, Lithuania"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Egle","family":"Gineikiene","sequence":"additional","affiliation":[{"name":"Center of Hematology, Oncology and Transfusion Medicine, Vilnius University Hospital Santaros Klinikos, LT-08661 Vilnius, Lithuania"},{"name":"Life Sciences Center, Vilnius University, LT-10257 Vilnius, Lithuania"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jonas","family":"Valantinas","sequence":"additional","affiliation":[{"name":"Center of Hepatology, Gastroenterology and Dietetics, Clinic of Gastroenterology, Nephrourology and Surgery, Vilnius University, LT-08661 Vilnius, Lithuania"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2018,9,27]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"2155","DOI":"10.1111\/liv.12818","article-title":"Global patterns of hepatocellular carcinoma management from diagnosis to death: The BRIDGE Study","volume":"35","author":"Park","year":"2015","journal-title":"Liver Int."},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"European Association for the Study of the Liver (2012). EASL-EORTC Clinical Practice Guidelines: Management of hepatocellular carcinoma. J. Hepatol., 56, 908\u2013943.","DOI":"10.1016\/j.jhep.2011.12.001"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1264","DOI":"10.1053\/j.gastro.2011.12.061","article-title":"Epidemiology of viral hepatitis and hepatocellular carcinoma","volume":"142","year":"2012","journal-title":"Gastroenterology"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"S58","DOI":"10.1016\/j.jhep.2014.07.012","article-title":"Natural history of hepatitis C","volume":"61","author":"Westbrook","year":"2014","journal-title":"J. Hepatol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"105","DOI":"10.3350\/cmh.2015.21.2.105","article-title":"Hepatitis C virus-induced hepatocellular carcinoma","volume":"21","author":"Goossens","year":"2015","journal-title":"Clin. Mol. Hepatol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"716","DOI":"10.1016\/j.jhep.2010.07.019","article-title":"IL-28B rs12979860 C\/T allele distribution in patients with liver cirrhosis: Role in the course of chronic viral hepatitis and the development of HCC","volume":"54","author":"Fabris","year":"2011","journal-title":"J. Hepatol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"687","DOI":"10.1111\/jvh.12533","article-title":"Epidemiology and outcomes of hepatitis C infection in elderly US Veterans","volume":"23","author":"Kramer","year":"2016","journal-title":"J. Viral Hepat."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"40","DOI":"10.7555\/JBR.30.20150002","article-title":"Impact of IL28B gene polymorphisms rs8099917 and rs12980275 on response to pegylated interferon-\u03b1\/ribavirin therapy in chronic hepatitis C genotype 4 patients","volume":"30","author":"Khattab","year":"2016","journal-title":"J. Biomed. Res."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"223","DOI":"10.1016\/j.cld.2011.03.006","article-title":"The global epidemiology of hepatocellular carcinoma: Present and future","volume":"15","author":"McGlynn","year":"2011","journal-title":"Clin. Liver Dis."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"96","DOI":"10.1007\/s00535-008-2258-6","article-title":"The epidemiology of hepatocellular cancer: From the perspectives of public health problem to tumor biology","volume":"44","author":"Caldwell","year":"2009","journal-title":"J. Gastroenterol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"PH28","DOI":"10.12659\/MSM.882511","article-title":"Anti-HCV prevalence in the general population of Lithuania","volume":"18","author":"Liakina","year":"2012","journal-title":"Med. Sci. Monit."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"32","DOI":"10.1002\/hep.21669","article-title":"FIB-4: An inexpensive and accurate marker of fibrosis in HCV infection. Comparison with liver biopsy and fibrotest","volume":"46","author":"Mallet","year":"2007","journal-title":"Hepatology"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"969","DOI":"10.1111\/j.1478-3231.2007.01519.x","article-title":"Noninvasive models to predict liver cirrhosis in patients with chronic hepatitis B","volume":"27","author":"Kim","year":"2007","journal-title":"Liver Int."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1009","DOI":"10.1111\/jgh.13236","article-title":"Development of hepatocellular carcinoma in patients with hepatitis C virus infection who achieved sustained virological response following interferon therapy: A large-scale, long-term cohort study","volume":"31","author":"Nagaoki","year":"2016","journal-title":"J. Gastroenterol. Hepatol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"S132","DOI":"10.1016\/S1542-3565(05)00700-7","article-title":"Molecular Basis of Hepatitis C Virus\u2013Associated Hepatocarcinogenesis: Lessons from Animal Model Studies","volume":"3","author":"Koike","year":"2005","journal-title":"Clin. Gastroenterol. Hepatol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"101","DOI":"10.1016\/j.coviro.2015.09.003","article-title":"How do persistent infections with hepatitis C virus cause liver cancer?","volume":"14","author":"Mitchell","year":"2015","journal-title":"Curr. Opin. Virol."},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Singal, A.G., Pillai, A., and Tiro, J. (2014). Early detection, curative treatment, and survival rates for hepatocellular carcinoma surveillance in patients with cirrhosis: A meta-analysis. PLoS Med., 11.","DOI":"10.1371\/journal.pmed.1001624"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"418","DOI":"10.1002\/hep.22375","article-title":"Estimation of stage-specific fibrosis progression rates in chronic hepatitis C virus infection: A meta-analysis and meta-regression","volume":"48","author":"Thein","year":"2008","journal-title":"Hepatology"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"947","DOI":"10.1097\/SLA.0000000000000710","article-title":"Recurrence of hepatocellular cancer after resection: Patterns, treatments, and prognosis","volume":"261","author":"Tabrizian","year":"2015","journal-title":"Ann. Surg."},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Kashuba, E., Kashuba, V., Sandalova, T., Klein, G., and Szekely, L. (2002). Epstein-Barr virus encoded nuclear protein EBNA-3 binds a novel human uridine kinase\/uracil phosphoribosyltransferase. BMC Cell Biol., 3.","DOI":"10.1186\/1471-2121-3-23"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1370","DOI":"10.1002\/1097-0142(19841001)54:7<1370::AID-CNCR2820540723>3.0.CO;2-5","article-title":"Enzymes of de novo and salvage pathways for pyrimidine biosynthesis in normal colon, colon carcinoma, and xenografts","volume":"54","author":"Ahmed","year":"1984","journal-title":"Cancer"},{"key":"ref_22","first-page":"1","article-title":"Increased uridine kinase (ATP: Uridine 5\u2032-phosphotransferase; EC 2.7.1.48) activity in human and rat tumors","volume":"16","author":"Shen","year":"1998","journal-title":"Cancer Biochem. Biophys."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"104","DOI":"10.1006\/bbrc.1999.1781","article-title":"Up-regulated uridine kinase gene identified by RLCS in the ventral horn after crush injury to rat sciatic nerves","volume":"266","author":"Yuh","year":"1999","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1227","DOI":"10.1007\/s10495-009-0385-z","article-title":"Downregulation of uridine-cytidine kinase like-1 decreases proliferation and enhances tumor susceptibility to lysis by apoptotic agents and natural killer cells","volume":"14","author":"Ambrose","year":"2009","journal-title":"Apoptosis"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"518","DOI":"10.1002\/hep.23691","article-title":"Effect of aging on risk for hepatocellular carcinoma in chronic hepatitis C virus infection","volume":"52","author":"Asahina","year":"2010","journal-title":"Hepatology"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"164","DOI":"10.1038\/ng.2521","article-title":"A variant upstream of IFNL3 (IL28B) creating a new interferon gene IFNL4 is associated with impaired clearance of hepatitis C virus","volume":"45","author":"Muchmore","year":"2013","journal-title":"Nat. Genet."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"3851","DOI":"10.1128\/JVI.79.6.3851-3854.2005","article-title":"Lambda interferon inhibits hepatitis B and C virus replication","volume":"79","author":"Robek","year":"2005","journal-title":"J. Virol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"591","DOI":"10.1089\/jir.2010.0066","article-title":"Preclinical and clinical development of pegylated interferon-lambda 1 in chronic hepatitis C","volume":"30","author":"Ramos","year":"2010","journal-title":"J. Interferon Cytokine Res."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"822","DOI":"10.1002\/hep.23743","article-title":"Phase 1b study of pegylated interferon-lambda 1 with or without ribavirin in patients with chronic genotype 1 hepatitis C virus infection","volume":"52","author":"Muir","year":"2010","journal-title":"Hepatology"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1152","DOI":"10.1007\/s00535-013-0858-2","article-title":"Genetic variation near interleukin 28B and the risk of hepatocellular carcinoma in patients with chronic hepatitis C","volume":"49","author":"Asahina","year":"2014","journal-title":"J. Gastroenterol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"748","DOI":"10.1007\/s00535-013-0826-x","article-title":"IL28B minor allele is associated with a younger age of onset of hepatocellular carcinoma in patients with chronic hepatitis C virus infection","volume":"49","author":"Sato","year":"2014","journal-title":"J. Gastroenterol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1827","DOI":"10.1158\/1078-0432.CCR-12-1641","article-title":"Association of interleukin-28B genotype and hepatocellular carcinoma recurrence in patients with chronic hepatitis C","volume":"19","author":"Hodo","year":"2013","journal-title":"Clin. Cancer Res."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"298","DOI":"10.1016\/j.humimm.2011.12.021","article-title":"Association of IL28B gene polymorphism with development of hepatocellular carcinoma in Japanese patients with chronic hepatitis C virus infection","volume":"73","author":"Joshita","year":"2012","journal-title":"Hum. Immunol."},{"key":"ref_34","first-page":"9245","article-title":"Polymorphisms in the IFNL3\/IL28B gene and hepatitis C: From adults to children","volume":"20","author":"Indolfi","year":"2014","journal-title":"World J. Gastroenterol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"859","DOI":"10.1016\/j.jhep.2010.08.020","article-title":"Interferon-lambda serum levels in hepatitis, C","volume":"54","author":"Langhans","year":"2011","journal-title":"J. Hepatol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"795","DOI":"10.1038\/ng.3836","article-title":"IFN-\u03bb3, not IFN-\u03bb4, likely mediates IFNL3-IFNL4 haplotype-dependent hepatic inflammation and fibrosis","volume":"49","author":"Eslam","year":"2017","journal-title":"Nat. Genet."},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"L\u00f3pez-Rodr\u00edguez, R., Hern\u00e1ndez-Bartolom\u00e9, \u00c1., Borque, M.J., Rodr\u00edguez-Mu\u00f1oz, Y., Mart\u00edn-V\u00edlchez, S., Garc\u00eda-Buey, L., Gonz\u00e1lez-Moreno, L., Real-Mart\u00ednez, Y., de Rueda, P.M., and Salmer\u00f3n, J. (2017). Interferon-related genetic markers of necroinflammatory activity in chronic hepatitis C. PLoS ONE, 12.","DOI":"10.1371\/journal.pone.0180927"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"597","DOI":"10.1089\/jir.2010.0058","article-title":"Interferon-lambda as a potential therapeutic agent in cancer treatment","volume":"30","author":"Steen","year":"2010","journal-title":"J. Interferon Cytokine Res."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1425","DOI":"10.1080\/14728222.2016.1241242","article-title":"Targeting IFN-\u03bb: Therapeutic implications","volume":"20","author":"Eslam","year":"2016","journal-title":"Expert Opin. Ther. Targets"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1466","DOI":"10.1007\/s11605-015-2850-z","article-title":"Local recurrence after radiofrequency ablation of hepatocellular carcinoma: Treatment choice and outcome","volume":"19","author":"Xie","year":"2015","journal-title":"J. Gastrointest. Surg."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"77","DOI":"10.1002\/hep.27259","article-title":"Global Distribution and Prevalence of Hepatitis C Virus Genotypes","volume":"61","author":"Messina","year":"2015","journal-title":"Hepatology"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"S45","DOI":"10.1016\/j.jhep.2014.07.027","article-title":"Global epidemiology and genotype distribution of the hepatitis C virus infection","volume":"61","author":"Gower","year":"2014","journal-title":"J. Hepatol."},{"key":"ref_43","first-page":"768470","article-title":"Correlation between genetic variations and serum level of interleukin 28B with virus genotypes and disease progression in chronic hepatitis C virus infection","volume":"2015","author":"Abdo","year":"2015","journal-title":"J. Immunol. Res."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"8757","DOI":"10.1007\/s13277-014-2142-3","article-title":"Influence of interleukin-28B polymorphism on progression to hepatitis virus-induced hepatocellular carcinoma","volume":"35","author":"He","year":"2014","journal-title":"Tumour Biol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"3708","DOI":"10.4238\/2013.September.19.1","article-title":"Association of the interleukin-28B gene polymorphism with development of hepatitis virus-related hepatocellular carcinoma and liver cirrhosis: A meta-analysis","volume":"12","author":"Suo","year":"2013","journal-title":"Genet. Mol. Res."},{"key":"ref_46","doi-asserted-by":"crossref","unstructured":"King, L.Y., Johnson, K.B., Zheng, H., Wei, L., Gudewicz, T., Hoshida, Y., Corey, K.E., Ajayi, T., Ufere, N., and Baumert, T.F. (2014). Host genetics predict clinical deterioration in HCV-related cirrhosis. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0114747"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"644","DOI":"10.1097\/TP.0b013e318244f774","article-title":"Role of IL28B polymorphism in the development of hepatitis C virus-induced hepatocellular carcinoma, graft fibrosis, and posttransplant antiviral therapy","volume":"93","author":"Eurich","year":"2012","journal-title":"Transplantation"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"279","DOI":"10.3109\/1354750X.2013.787544","article-title":"The kinin-kallikrein system: Physiological roles, pathophysiology and its relationship to cancer biomarkers","volume":"18","author":"Kashuba","year":"2013","journal-title":"Biomarkers"}],"container-title":["Medicina"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1648-9144\/54\/5\/67\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T15:22:51Z","timestamp":1760196171000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1648-9144\/54\/5\/67"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2018,9,27]]},"references-count":48,"journal-issue":{"issue":"5","published-online":{"date-parts":[[2018,11]]}},"alternative-id":["medicina54050067"],"URL":"https:\/\/doi.org\/10.3390\/medicina54050067","relation":{},"ISSN":["1648-9144"],"issn-type":[{"type":"electronic","value":"1648-9144"}],"subject":[],"published":{"date-parts":[[2018,9,27]]}}}