{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,29]],"date-time":"2026-04-29T20:33:37Z","timestamp":1777494817089,"version":"3.51.4"},"reference-count":49,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"6","license":[{"start":{"date-parts":[[2018,1,18]],"date-time":"2018-01-18T00:00:00Z","timestamp":1516233600000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"},{"start":{"date-parts":[[2018,1,18]],"date-time":"2018-01-18T00:00:00Z","timestamp":1516233600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":["lww.com","ovid.com"],"crossmark-restriction":true},"short-container-title":["Hepatology"],"published-print":{"date-parts":[[2018,6]]},"abstract":"<jats:p>Fibrosis and cancer represent two major complications of chronic liver disease. MicroRNAs have been implicated in the development of fibrosis and cancer, thus constituting potential therapeutic targets. Here, we investigated the role of microRNA\u201021 (miR\u201021), a microRNA that has been implicated in the development of fibrosis in multiple organs and has also been suggested to act as an \u201concomir.\u201d Accordingly, miR\u201021 was the microRNA that showed the strongest up\u2010regulation in activated hepatic stellate cells (HSCs) in multiple models of fibrogenesis, with an 8\u2010fold to 24\u2010fold induction compared to quiescent HSCs. However, miR\u201021 antisense inhibition did not suppress the activation of murine or human HSCs in culture or in liver slices. Moreover, genetic deletion of miR\u201021 in two independently generated knockout mice or miR\u201021 antisense inhibition did not alter HSC activation or liver fibrosis in models of toxic and biliary liver injury. Despite a strong up\u2010regulation of miR\u201021 in injury\u2010associated hepatocellular carcinoma and in cholangiocarcinoma, miR\u201021 deletion or antisense inhibition did not reduce the development of liver tumors. As inhibition of the most up\u2010regulated microRNA did not affect HSC activation, liver fibrosis, or fibrosis\u2010associated liver cancer, we additionally tested the role of microRNAs in HSCs by HSC\u2010specific Dicer deletion. Although Dicer deletion decreased microRNA expression in HSCs and altered the expression of select genes, it only exerted negligible effects on HSC activation and liver fibrosis.<jats:italic toggle=\"yes\">Conclusion<\/jats:italic>: Genetic and pharmacologic manipulation of miR\u201021 does not inhibit the development of liver fibrosis and liver cancer. Moreover, suppression of microRNA synthesis does not significantly affect HSC phenotype and activation. (H<jats:sc>epatology<\/jats:sc>2018;67:2414\u20102429).<\/jats:p>","DOI":"10.1002\/hep.29627","type":"journal-article","created":{"date-parts":[[2017,11,1]],"date-time":"2017-11-01T20:20:02Z","timestamp":1509567602000},"page":"2414-2429","update-policy":"https:\/\/doi.org\/10.1097\/lww.0000000000001000","source":"Crossref","is-referenced-by-count":72,"title":["MicroRNA\u201021 and Dicer are dispensable for hepatic stellate cell activation and the development of liver fibrosis"],"prefix":"10.1097","volume":"67","author":[{"given":"Jorge Matias","family":"Caviglia","sequence":"first","affiliation":[{"name":"Department of Medicine,Columbia University,New York,NY"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jun","family":"Yan","sequence":"additional","affiliation":[{"name":"Department of Medicine,Columbia University,New York,NY"},{"name":"Department of Pathology,Tianjin First Center Hospital,Tianjin,China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Myoung\u2010Kuk","family":"Jang","sequence":"additional","affiliation":[{"name":"Department of Medicine,Columbia University,New York,NY"},{"name":"Department of Gastroenterology and Hepatology, Internal Medicine,Kangdong Sacred Heart Hospital of Hallym University Medical Center,Seoul,South Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Geum\u2010Youn","family":"Gwak","sequence":"additional","affiliation":[{"name":"Department of Medicine,Columbia University,New York,NY"},{"name":"Department of Medicine, Samsung Medical Center,Sungkyunkwan University School of Medicine,Seoul,Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Silvia","family":"Affo","sequence":"additional","affiliation":[{"name":"Department of Medicine,Columbia University,New York,NY"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lexing","family":"Yu","sequence":"additional","affiliation":[{"name":"Department of Medicine,Columbia University,New York,NY"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Peter","family":"Olinga","sequence":"additional","affiliation":[{"name":"Division of Pharmaceutical Technology and Biopharmacy, Department of Pharmacy,University of Groningen,Groningen,the Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Richard A.","family":"Friedman","sequence":"additional","affiliation":[{"name":"Biomedical Informatics Shared Resource, Herbert Irving Comprehensive Cancer Center and Department of Biomedical Informatics,Columbia University,New York,NY"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xin","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Bioengineering and Therapeutic Sciences and Liver Center,University of California San Francisco,San Francisco,CA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Robert F.","family":"Schwabe","sequence":"additional","affiliation":[{"name":"Department of Medicine,Columbia University,New York,NY"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"276","published-online":{"date-parts":[[2018,1,18]]},"reference":[{"key":"hep29627-bib-0001-20241017","doi-asserted-by":"crossref","first-page":"2823","DOI":"10.1038\/ncomms3823","article-title":"Fate tracing reveals hepatic stellate cells as dominant contributors to liver fibrosis independent of its aetiology","volume":"4","year":"2013","journal-title":"Nat Commun"},{"key":"hep29627-bib-0002-20241017","doi-asserted-by":"crossref","first-page":"1473","DOI":"10.1002\/j.2040-4603.2013.tb00529.x","article-title":"Hepatic stellate cells and liver fibrosis","volume":"3","year":"2013","journal-title":"Compr Physiol"},{"key":"hep29627-bib-0003-20241017","doi-asserted-by":"crossref","first-page":"97","DOI":"10.1055\/s-0035-1550061","article-title":"Origin and function of myofibroblasts in the liver","volume":"35","year":"2015","journal-title":"Semin Liver Dis"},{"key":"hep29627-bib-0004-20241017","doi-asserted-by":"crossref","first-page":"425","DOI":"10.1146\/annurev-pathol-011110-130246","article-title":"Pathogenesis of liver fibrosis","volume":"6","year":"2011","journal-title":"Annu Rev Pathol"},{"key":"hep29627-bib-0005-20241017","first-page":"209","article-title":"The role of miRNAs in stress\u2010responsive hepatic stellate cells during liver fibrosis","volume":"6","year":"2015","journal-title":"Front Physiol"},{"key":"hep29627-bib-0006-20241017","doi-asserted-by":"crossref","first-page":"542","DOI":"10.1038\/nrgastro.2013.87","article-title":"MicroRNAs in liver disease","volume":"10","year":"2013","journal-title":"Nat Rev Gastroenterol Hepatol"},{"key":"hep29627-bib-0007-20241017","doi-asserted-by":"crossref","first-page":"1431","DOI":"10.1053\/j.gastro.2012.04.007","article-title":"MicroRNAs in liver disease","volume":"142","year":"2012","journal-title":"Gastroenterology"},{"key":"hep29627-bib-0008-20241017","doi-asserted-by":"crossref","first-page":"421","DOI":"10.1038\/nrg3965","article-title":"Towards a molecular understanding of microRNA\u2010mediated gene silencing","volume":"16","year":"2015","journal-title":"Nat Rev Genet"},{"key":"hep29627-bib-0009-20241017","doi-asserted-by":"crossref","first-page":"515","DOI":"10.1016\/j.cell.2012.04.005","article-title":"Roles for microRNAs in conferring robustness to biological processes","volume":"149","year":"2012","journal-title":"Cell"},{"key":"hep29627-bib-0010-20241017","doi-asserted-by":"crossref","first-page":"1172","DOI":"10.1016\/j.cell.2012.02.005","article-title":"MicroRNAs in stress signaling and human disease","volume":"148","year":"2012","journal-title":"Cell"},{"key":"hep29627-bib-0011-20241017","doi-asserted-by":"crossref","first-page":"1297","DOI":"10.1152\/physrev.00041.2015","article-title":"Non\u2010coding RNAs in development and disease: background, mechanisms, and therapeutic approaches","volume":"96","year":"2016","journal-title":"Physiol Rev"},{"key":"hep29627-bib-0012-20241017","doi-asserted-by":"crossref","first-page":"1589","DOI":"10.1084\/jem.20100035","article-title":"miR\u201021 mediates fibrogenic activation of pulmonary fibroblasts and lung fibrosis","volume":"207","year":"2010","journal-title":"J Exp Med"},{"key":"hep29627-bib-0013-20241017","first-page":"121ra118","article-title":"MicroRNA\u201021 promotes fibrosis of the kidney by silencing metabolic pathways","volume":"4","year":"2012","journal-title":"Sci Transl Med"},{"key":"hep29627-bib-0014-20241017","doi-asserted-by":"crossref","first-page":"980","DOI":"10.1038\/nature07511","article-title":"MicroRNA\u201021 contributes to myocardial disease by stimulating MAP kinase signalling in fibroblasts","volume":"456","year":"2008","journal-title":"Nature"},{"key":"hep29627-bib-0015-20241017","doi-asserted-by":"crossref","first-page":"3912","DOI":"10.1172\/JCI43604","article-title":"Stress\u2010dependent cardiac remodeling occurs in the absence of microRNA\u201021 in mice","volume":"120","year":"2010","journal-title":"J Clin Invest"},{"key":"hep29627-bib-0016-20241017","doi-asserted-by":"crossref","first-page":"461","DOI":"10.1172\/JCI45938","article-title":"Comparison of different miR\u201021 inhibitor chemistries in a cardiac disease model","volume":"121","year":"2011","journal-title":"J Clin Invest"},{"key":"hep29627-bib-0017-20241017","doi-asserted-by":"crossref","first-page":"462","DOI":"10.1172\/JCI46108","article-title":"Response to Thum et al","volume":"121","year":"2011","journal-title":"J Clin Invest"},{"key":"hep29627-bib-0018-20241017","doi-asserted-by":"crossref","first-page":"R762","DOI":"10.1016\/j.cub.2014.06.043","article-title":"Aberrant regulation and function of microRNAs in cancer","volume":"24","year":"2014","journal-title":"Curr Biol"},{"key":"hep29627-bib-0019-20241017","doi-asserted-by":"crossref","first-page":"259","DOI":"10.1038\/nrc1840","article-title":"Oncomirs \u2010 microRNAs with a role in cancer","volume":"6","year":"2006","journal-title":"Nat Rev Cancer"},{"key":"hep29627-bib-0020-20241017","doi-asserted-by":"crossref","first-page":"86","DOI":"10.1038\/nature09284","article-title":"OncomiR addiction in an in vivo model of microRNA\u201021\u2010induced pre\u2010B\u2010cell lymphoma","volume":"467","year":"2010","journal-title":"Nature"},{"key":"hep29627-bib-0021-20241017","doi-asserted-by":"crossref","first-page":"1097","DOI":"10.1172\/JCI46039","article-title":"A microRNA\u201021 surge facilitates rapid cyclin D1 translation and cell cycle progression in mouse liver regeneration","volume":"122","year":"2012","journal-title":"J Clin Invest"},{"key":"hep29627-bib-0022-20241017","doi-asserted-by":"crossref","first-page":"1256","DOI":"10.1038\/labinvest.2016.112","article-title":"Knockout of microRNA\u201021 reduces biliary hyperplasia and liver fibrosis in cholestatic bile duct ligated mice","volume":"96","year":"2016","journal-title":"Lab Invest"},{"key":"hep29627-bib-0023-20241017","doi-asserted-by":"crossref","first-page":"1859","DOI":"10.1158\/0008-5472.CAN-14-1254","article-title":"miR\u201021 Inhibition reduces liver fibrosis and prevents tumor development by inducing apoptosis of CD24+ progenitor cells","volume":"75","year":"2015","journal-title":"Cancer Res"},{"key":"hep29627-bib-0024-20241017","doi-asserted-by":"crossref","first-page":"37082","DOI":"10.1074\/jbc.M113.517953","article-title":"The autoregulatory feedback loop of microRNA\u201021\/programmed cell death protein 4\/activation protein\u20101 (MiR\u201021\/PDCD4\/AP\u20101) as a driving force for hepatic fibrosis development","volume":"288","year":"2013","journal-title":"J Biol Chem"},{"key":"hep29627-bib-0025-20241017","doi-asserted-by":"crossref","first-page":"11549","DOI":"10.1038\/srep11549","article-title":"Integrative miRNA and gene expression profiling analysis of human quiescent hepatic stellate cells","volume":"5","year":"2015","journal-title":"Sci Rep"},{"key":"hep29627-bib-0026-20241017","doi-asserted-by":"crossref","first-page":"282","DOI":"10.1016\/j.ccr.2010.08.013","article-title":"Modulation of K\u2010Ras\u2010dependent lung tumorigenesis by microRNA\u201021","volume":"18","year":"2010","journal-title":"Cancer Cell"},{"key":"hep29627-bib-0027-20241017","doi-asserted-by":"crossref","first-page":"10144","DOI":"10.1073\/pnas.1103735108","article-title":"Loss of the miR\u201021 allele elevates the expression of its target genes and reduces tumorigenesis","volume":"108","year":"2011","journal-title":"Proc Natl Acad Sci U S A"},{"key":"hep29627-bib-0028-20241017","doi-asserted-by":"crossref","first-page":"10898","DOI":"10.1073\/pnas.0504834102","article-title":"The RNaseIII enzyme Dicer is required for morphogenesis but not patterning of the vertebrate limb","volume":"102","year":"2005","journal-title":"Proc Natl Acad Sci U S A"},{"key":"hep29627-bib-0029-20241017","doi-asserted-by":"crossref","first-page":"720","DOI":"10.1053\/j.gastro.2015.11.039","article-title":"Epithelial transforming growth factor\u2010beta signaling does not contribute to liver fibrosis but protects mice from cholangiocarcinoma","volume":"150","year":"2016","journal-title":"Gastroenterology"},{"key":"hep29627-bib-0030-20241017","doi-asserted-by":"crossref","first-page":"305","DOI":"10.1038\/nprot.2015.017","article-title":"High\u2010yield and high\u2010purity isolation of hepatic stellate cells from normal and fibrotic mouse livers","volume":"10","year":"2015","journal-title":"Nat Protoc"},{"key":"hep29627-bib-0031-20241017","doi-asserted-by":"crossref","first-page":"1461","DOI":"10.1002\/hep.26429","article-title":"Hepatic macrophages but not dendritic cells contribute to liver fibrosis by promoting the survival of activated hepatic stellate cells in mice","volume":"58","year":"2013","journal-title":"Hepatology"},{"key":"hep29627-bib-0032-20241017","doi-asserted-by":"crossref","first-page":"1937","DOI":"10.1053\/j.gastro.2007.02.033","article-title":"Gene expression profiles during hepatic stellate cell activation in culture and in vivo","volume":"132","year":"2007","journal-title":"Gastroenterology"},{"key":"hep29627-bib-0033-20241017","article-title":"Pan\u2010mTOR inhibitor MLN0128 is effective against intrahepatic cholangiocarcinoma in mice","year":"2017","journal-title":"J Hepatol"},{"key":"hep29627-bib-0034-20241017","doi-asserted-by":"crossref","first-page":"1510","DOI":"10.1261\/rna.033308.112","article-title":"Disease\u2010linked microRNA\u201021 exhibits drastically reduced mRNA binding and silencing activity in healthy mouse liver","volume":"18","year":"2012","journal-title":"RNA"},{"key":"hep29627-bib-0035-20241017","doi-asserted-by":"crossref","first-page":"272","DOI":"10.1016\/j.jhep.2005.02.035","article-title":"Genomic and functional characterization of stellate cells isolated from human cirrhotic livers","volume":"43","year":"2005","journal-title":"J Hepatol"},{"key":"hep29627-bib-0036-20241017","doi-asserted-by":"crossref","first-page":"1540","DOI":"10.1038\/nprot.2010.111","article-title":"Preparation and incubation of precision\u2010cut liver and intestinal slices for application in drug metabolism and toxicity studies","volume":"5","year":"2010","journal-title":"Nat Protoc"},{"key":"hep29627-bib-0037-20241017","doi-asserted-by":"crossref","first-page":"126","DOI":"10.1038\/nrm2632","article-title":"Biogenesis of small RNAs in animals","volume":"10","year":"2009","journal-title":"Nat Rev Mol Cell Biol"},{"key":"hep29627-bib-0038-20241017","doi-asserted-by":"crossref","first-page":"363","DOI":"10.1038\/35053110","article-title":"Role for a bidentate ribonuclease in the initiation step of RNA interference","volume":"409","year":"2001","journal-title":"Nature"},{"key":"hep29627-bib-0039-20241017","doi-asserted-by":"crossref","first-page":"153","DOI":"10.1146\/annurev-pathol-052016-100322","article-title":"The role of cancer\u2010associated fibroblasts and fibrosis in liver cancer","volume":"12","year":"2017","journal-title":"Annu Rev Pathol"},{"issue":"Suppl. 1","key":"hep29627-bib-0040-20241017","first-page":"S35","article-title":"Hepatocellular carcinoma in cirrhosis: incidence and risk factors","volume":"127","year":"2004","journal-title":"Gastroenterology"},{"key":"hep29627-bib-0041-20241017","doi-asserted-by":"crossref","first-page":"1955","DOI":"10.1002\/hep.22256","article-title":"MicroRNA profiling in hepatocellular tumors is associated with clinical features and oncogene\/tumor suppressor gene mutations","volume":"47","year":"2008","journal-title":"Hepatology"},{"key":"hep29627-bib-0042-20241017","doi-asserted-by":"crossref","first-page":"647","DOI":"10.1053\/j.gastro.2007.05.022","article-title":"MicroRNA\u201021 regulates expression of the PTEN tumor suppressor gene in human hepatocellular cancer","volume":"133","year":"2007","journal-title":"Gastroenterology"},{"key":"hep29627-bib-0043-20241017","doi-asserted-by":"crossref","first-page":"1595","DOI":"10.1002\/hep.22838","article-title":"MicroRNA\u201021 is overexpressed in human cholangiocarcinoma and regulates programmed cell death 4 and tissue inhibitor of metalloproteinase 3","volume":"49","year":"2009","journal-title":"Hepatology"},{"key":"hep29627-bib-0044-20241017","doi-asserted-by":"crossref","first-page":"504","DOI":"10.1016\/j.ccr.2012.02.007","article-title":"Promotion of hepatocellular carcinoma by the intestinal microbiota and TLR4","volume":"21","year":"2012","journal-title":"Cancer Cell"},{"key":"hep29627-bib-0045-20241017","doi-asserted-by":"crossref","first-page":"805","DOI":"10.1681\/ASN.2013121274","article-title":"MicroRNA\u201021 in glomerular injury","volume":"26","year":"2015","journal-title":"J Am Soc Nephrol"},{"key":"hep29627-bib-0046-20241017","doi-asserted-by":"crossref","first-page":"e0181950","DOI":"10.1371\/journal.pone.0181950","article-title":"Absence of microRNA\u201021 does not reduce muscular dystrophy in mouse models of LAMA2\u2010CMD","volume":"12","year":"2017","journal-title":"PLoS One"},{"key":"hep29627-bib-0047-20241017","doi-asserted-by":"crossref","first-page":"575","DOI":"10.1126\/science.1139089","article-title":"Control of stress\u2010dependent cardiac growth and gene expression by a microRNA","volume":"316","year":"2007","journal-title":"Science"},{"key":"hep29627-bib-0048-20241017","doi-asserted-by":"crossref","first-page":"209","DOI":"10.1002\/hep.23922","article-title":"Micro\u2010RNA profiling reveals a role for miR\u201029 in human and murine liver fibrosis","volume":"53","year":"2011","journal-title":"Hepatology"},{"key":"hep29627-bib-0049-20241017","doi-asserted-by":"crossref","first-page":"765","DOI":"10.1053\/j.gastro.2014.07.018","article-title":"Cell death and cell death responses in liver disease: mechanisms and clinical relevance","volume":"147","year":"2014","journal-title":"Gastroenterology"}],"container-title":["Hepatology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1002%2Fhep.29627","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/journals.lww.com\/01515467-201806000-00036","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,6,26]],"date-time":"2025-06-26T20:46:10Z","timestamp":1750970770000},"score":1,"resource":{"primary":{"URL":"https:\/\/journals.lww.com\/01515467-201806000-00036"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2018,1,18]]},"references-count":49,"journal-issue":{"issue":"6","published-print":{"date-parts":[[2018]]}},"URL":"https:\/\/doi.org\/10.1002\/hep.29627","relation":{},"ISSN":["0270-9139","1527-3350"],"issn-type":[{"value":"0270-9139","type":"print"},{"value":"1527-3350","type":"electronic"}],"subject":[],"published":{"date-parts":[[2018,1,18]]},"assertion":[{"value":"2016-12-31","name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2017-10-30","name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}}]}}