{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,19]],"date-time":"2026-01-19T15:05:07Z","timestamp":1768835107018,"version":"3.49.0"},"reference-count":37,"publisher":"MDPI AG","issue":"14","license":[{"start":{"date-parts":[[2024,7,18]],"date-time":"2024-07-18T00:00:00Z","timestamp":1721260800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100009619","name":"Japan Agency for Medical Research and Development","doi-asserted-by":"publisher","award":["JP22fk0310503"],"award-info":[{"award-number":["JP22fk0310503"]}],"id":[{"id":"10.13039\/100009619","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Risk factors for hepatocarcinogenesis include chronic inflammation due to viral infection, liver fibrosis, and aging. In this study, we separated carcinogenic and non-carcinogenic cases due to hepatitis C virus (HCV) infection, aiming to comprehensively analyze miRNA expression in liver tissues by age, and identify factors that contribute to carcinogenesis. Total RNA was extracted from 360 chronic hepatitis C (CH), 43 HCV infected hepatocellular carcinoma (HCC), and surrounding non-tumor (SNT) tissues. MicroRNA (miRNA) expression patterns were analyzed using microarray. Using machine learning, we extracted characteristic miRNA expression patterns for each disease and age. There were no age-dependent changes in miRNA expression in the disease-specific comparisons; however, miRNA expression differed among the age groups of 50, 60, and 70 years of age between CH and SNT. The expression of miRNA was different between SNT and HCC only in patients in their 70s. Of the 55 miRNAs with significant differences in expression between CH and SNT, 34 miRNAs showed significant differences in expression even in the degree of liver fibrosis. The observation that miRNAs involved in hepatocarcinogenesis differ at different ages suggests that the mechanisms of carcinogenesis differ by age group as well. We also found that many miRNAs whose expression did not affect liver fibrosis were involved in carcinogenesis. These findings are expected to define biomarkers for detection of HCC at early stage, and develop novel therapeutic targets for HCC.<\/jats:p>","DOI":"10.3390\/ijms25147858","type":"journal-article","created":{"date-parts":[[2024,7,18]],"date-time":"2024-07-18T10:39:26Z","timestamp":1721299166000},"page":"7858","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Analysis of Carcinogenic Involvement of MicroRNA Pattern in Peripheral Non-Cancerous Tissues and Chronic Viral Liver Injury"],"prefix":"10.3390","volume":"25","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0123-8921","authenticated-orcid":false,"given":"Tomohiro","family":"Umezu","sequence":"first","affiliation":[{"name":"Department of Molecular Pathology, Tokyo Medical University, 6-1-1 Shinjuku, Shinjuku-ku, Tokyo 160-8402, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tomoya","family":"Mori","sequence":"additional","affiliation":[{"name":"Bioinformatics Center, Institute for Chemical Research, Kyoto University, Gokasho, Uji, Kyoto 611-0011, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1652-6168","authenticated-orcid":false,"given":"Hidenori","family":"Toyoda","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology, Ogaki Municipal Hospital, 4-86 Minaminokawa-cho, Ogaki, Gifu 503-8502, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2901-9595","authenticated-orcid":false,"given":"Kohsuke","family":"Kanekura","sequence":"additional","affiliation":[{"name":"Department of Molecular Pathology, Tokyo Medical University, 6-1-1 Shinjuku, Shinjuku-ku, Tokyo 160-8402, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9119-4864","authenticated-orcid":false,"given":"Akihiro","family":"Tamori","sequence":"additional","affiliation":[{"name":"Department of Hepatology, Osaka Metropolitan University Graduate School of Medicine, 1-4-3 Asahimachi, Abeno-ku, Osaka 545-8585, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Takahiro","family":"Ochiya","sequence":"additional","affiliation":[{"name":"Institution of Medical Science, Tokyo Medical University, 6-7-1 Nishishinjuku, Shinjuku-ku, Tokyo 160-0023, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7052-4289","authenticated-orcid":false,"given":"Masahiko","family":"Kuroda","sequence":"additional","affiliation":[{"name":"Department of Molecular Pathology, Tokyo Medical University, 6-1-1 Shinjuku, Shinjuku-ku, Tokyo 160-8402, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9763-797X","authenticated-orcid":false,"given":"Tatsuya","family":"Akutsu","sequence":"additional","affiliation":[{"name":"Bioinformatics Center, Institute for Chemical Research, Kyoto University, Gokasho, Uji, Kyoto 611-0011, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yoshiki","family":"Murakami","sequence":"additional","affiliation":[{"name":"Department of Molecular Pathology, Tokyo Medical University, 6-1-1 Shinjuku, Shinjuku-ku, Tokyo 160-8402, Japan"},{"name":"Department of Dentistry, Asahi University, 3-23 Hashimoto-cho, Gifu 500-8523, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2024,7,18]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"394","DOI":"10.3322\/caac.21492","article-title":"Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries","volume":"68","author":"Bray","year":"2018","journal-title":"CA Cancer J. Clin."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1485","DOI":"10.1200\/JCO.2008.20.7753","article-title":"Hepatocellular carcinoma incidence, mortality, and survival trends in the United States from 1975 to 2005","volume":"27","author":"Altekruse","year":"2009","journal-title":"J. Clin. Oncol."},{"key":"ref_3","first-page":"851","article-title":"Clinical characteristics of hepatocellular carcinoma in elderly patients","volume":"2","author":"Honda","year":"2011","journal-title":"Oncol. Lett."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"655","DOI":"10.1038\/nrc1675","article-title":"Cancer and ageing: A nexus at several levels","volume":"5","author":"Balducci","year":"2005","journal-title":"Nat. Rev. Cancer"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"277","DOI":"10.3322\/caac.20073","article-title":"Cancer statistics, 2010","volume":"60","author":"Jemal","year":"2010","journal-title":"CA Cancer J. Clin."},{"key":"ref_6","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_7","doi-asserted-by":"crossref","first-page":"297","DOI":"10.1002\/hep.1840090222","article-title":"The effect of age upon liver volume and apparent liver blood flow in healthy man","volume":"9","author":"Wynne","year":"1989","journal-title":"Hepatology"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"907","DOI":"10.1111\/j.1365-2125.1976.tb00646.x","article-title":"The relationship between liver volume, antipyrine clearance and indocyanine green clearance before and after phenobarbitone administration in man","volume":"3","author":"Roberts","year":"1976","journal-title":"Br. J. Clin. Pharmacol."},{"key":"ref_9","first-page":"43","article-title":"The use of indocyanine green in the measurement of hepatic blood flow and as a test of hepatic function","volume":"21","author":"Caesar","year":"1961","journal-title":"Clin. Sci."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"203","DOI":"10.1038\/nrd.2016.246","article-title":"MicroRNA therapeutics: Towards a new era for the management of cancer and other diseases","volume":"16","author":"Rupaimoole","year":"2017","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Tutar, Y. (2014). miRNA and cancer; computational and experimental approaches. Curr. Pharm. Biotechnol., 15.","DOI":"10.2174\/138920101505140828161335"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"235","DOI":"10.1111\/j.1474-9726.2006.00210.x","article-title":"Modulated microRNA expression during adult lifespan in Caenorhabditis elegans","volume":"5","author":"Yang","year":"2006","journal-title":"Aging Cell"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"2159","DOI":"10.1016\/j.cub.2010.11.015","article-title":"MicroRNAs both promote and antagonize longevity in C","volume":"20","author":"Pincus","year":"2010","journal-title":"elegans. Curr. Biol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1804","DOI":"10.1261\/rna.2714411","article-title":"Age-associated changes in expression of small, noncoding RNAs, including microRNAs, in C","volume":"17","author":"Kato","year":"2011","journal-title":"elegans. RNA"},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Ibanez-Ventoso, C., Vora, M., and Driscoll, M. (2008). Sequence relationships among C. elegans, D. melanogaster and human microRNAs highlight the extensive conservation of microRNAs in biology. PLoS ONE, 3.","DOI":"10.1371\/journal.pone.0002818"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"534","DOI":"10.1016\/j.mad.2008.05.004","article-title":"Murine microRNAs implicated in liver functions and aging process","volume":"129","author":"Maes","year":"2008","journal-title":"Mech. Ageing Dev."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"75","DOI":"10.1016\/j.mad.2010.12.004","article-title":"Increased expression of miR-34a and miR-93 in rat liver during aging, and their impact on the expression of Mgst1 and Sirt1","volume":"132","author":"Li","year":"2011","journal-title":"Mech. Ageing Dev."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1111\/j.1474-9726.2009.00529.x","article-title":"MicroRNA regulation in Ames dwarf mouse liver may contribute to delayed aging","volume":"9","author":"Bates","year":"2010","journal-title":"Aging Cell"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1473","DOI":"10.1016\/j.stem.2021.03.017","article-title":"Decline in IGF1 in the bone marrow microenvironment initiates hematopoietic stem cell aging","volume":"28","author":"Young","year":"2021","journal-title":"Cell Stem Cell"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"16268","DOI":"10.1073\/pnas.1002696107","article-title":"Insulin-like growth factor 1 treatment extends longevity in a mouse model of human premature aging by restoring somatotroph axis function","volume":"107","author":"Marino","year":"2010","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"232","DOI":"10.1016\/j.ccr.2011.01.001","article-title":"Identification of miRNomes in human liver and hepatocellular carcinoma reveals miR-199a\/b-3p as therapeutic target for hepatocellular carcinoma","volume":"19","author":"Hou","year":"2011","journal-title":"Cancer Cell"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"671","DOI":"10.1002\/jcb.20982","article-title":"Downregulation of miR-122 in the rodent and human hepatocellular carcinomas","volume":"99","author":"Kutay","year":"2006","journal-title":"J. Cell Biochem."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"6092","DOI":"10.1158\/0008-5472.CAN-06-4607","article-title":"Cyclin G1 is a target of miR-122a, a microRNA frequently down-regulated in human hepatocellular carcinoma","volume":"67","author":"Gramantieri","year":"2007","journal-title":"Cancer Res."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"3526","DOI":"10.1038\/onc.2009.211","article-title":"Loss of miR-122 expression in liver cancer correlates with suppression of the hepatic phenotype and gain of metastatic properties","volume":"28","author":"Coulouarn","year":"2009","journal-title":"Oncogene"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"2537","DOI":"10.1038\/sj.onc.1209283","article-title":"Comprehensive analysis of microRNA expression patterns in hepatocellular carcinoma and non-tumorous tissues","volume":"25","author":"Murakami","year":"2006","journal-title":"Oncogene"},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Murakami, Y., Tamori, A., Itami, S., Tanahashi, T., Toyoda, H., Tanaka, M., Wu, W., Brojigin, N., Kaneoka, Y., and Maeda, A. (2013). The expression level of miR-18b in hepatocellular carcinoma is associated with the grade of malignancy and prognosis. BMC Cancer, 13.","DOI":"10.1186\/1471-2407-13-99"},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Sato, F., Hatano, E., Kitamura, K., Myomoto, A., Fujiwara, T., Takizawa, S., Tsuchiya, S., Tsujimoto, G., Uemoto, S., and Shimizu, K. (2011). MicroRNA profile predicts recurrence after resection in patients with hepatocellular carcinoma within the Milan Criteria. PLoS ONE, 6.","DOI":"10.1371\/journal.pone.0016435"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"174","DOI":"10.7326\/0003-4819-131-3-199908030-00003","article-title":"Interferon therapy reduces the risk for hepatocellular carcinoma: National surveillance program of cirrhotic and noncirrhotic patients with chronic hepatitis C in Japan. IHIT Study Group. Inhibition of Hepatocarcinogenesis by Interferon Therapy","volume":"131","author":"Yoshida","year":"1999","journal-title":"Ann. Intern. Med."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1518","DOI":"10.1002\/hep.21408","article-title":"Prediction of recurrence of hepatocellular carcinoma after curative ablation using three tumor markers","volume":"44","author":"Tateishi","year":"2006","journal-title":"Hepatology"},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Ghafouri-Fard, S., Abak, A., Talebi, S.F., Shoorei, H., Branicki, W., Taheri, M., and Akbari Dilmaghani, N. (2021). Role of miRNA and lncRNAs in organ fibrosis and aging. Biomed. Pharmacother., 143.","DOI":"10.1016\/j.biopha.2021.112132"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"155436","DOI":"10.1016\/j.cyto.2021.155436","article-title":"MiR-325-3p mediate the CXCL17\/CXCR8 axis to regulate angiogenesis in hepatocellular carcinoma","volume":"141","author":"Li","year":"2021","journal-title":"Cytokine"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"16","DOI":"10.1016\/j.canlet.2021.12.026","article-title":"SP1-induced lncRNA DUBR promotes stemness and oxaliplatin resistance of hepatocellular carcinoma via E2F1-CIP2A feedback","volume":"528","author":"Liu","year":"2022","journal-title":"Cancer Lett."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"229","DOI":"10.3892\/ol.2021.12490","article-title":"Association between microRNA-527 and glypican-3 in hepatocellular carcinoma","volume":"21","author":"Nomura","year":"2021","journal-title":"Oncol. Lett."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"5823","DOI":"10.1007\/s00432-022-04544-7","article-title":"Bacterial metabolite butyrate in modulating sorafenib-targeted microRNAs to curtail its resistance in hepatocellular carcinoma","volume":"149","author":"Kumar","year":"2022","journal-title":"J. Cancer Res. Clin. Oncol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"R51","DOI":"10.1186\/bcr1542","article-title":"Comparison of gene expression profiles in core biopsies and corresponding surgical breast cancer samples","volume":"8","author":"Vuaroqueaux","year":"2006","journal-title":"Breast Cancer Res."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"451","DOI":"10.1007\/s10549-019-05141-y","article-title":"Real-world data on discordance between estrogen, progesterone, and HER2 receptor expression on diagnostic tumor biopsy versus tumor resection material","volume":"175","author":"Berghuis","year":"2019","journal-title":"Breast Cancer Res. Treat."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"e47","DOI":"10.1093\/nar\/gkv007","article-title":"Limma powers differential expression analyses for RNA-sequencing and microarray studies","volume":"43","author":"Ritchie","year":"2015","journal-title":"Nucleic Acids Res."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/25\/14\/7858\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T15:18:50Z","timestamp":1760109530000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/25\/14\/7858"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,7,18]]},"references-count":37,"journal-issue":{"issue":"14","published-online":{"date-parts":[[2024,7]]}},"alternative-id":["ijms25147858"],"URL":"https:\/\/doi.org\/10.3390\/ijms25147858","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,7,18]]}}}