{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,26]],"date-time":"2026-10-26T11:48:38Z","timestamp":1793015318841,"version":"4.5.0"},"reference-count":35,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2017,4,6]],"date-time":"2017-04-06T00:00:00Z","timestamp":1491436800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2017,4,6]],"date-time":"2017-04-06T00:00:00Z","timestamp":1491436800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Sci Rep"],"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Tissue inhibitor of metalloproteinases-1 (TIMP-1) is upregulated during hepatic fibrogenesis and considered to promote fibrosis in the injured liver by inhibition of matrix metalloproteases (MMP) and degradation of extracellular matrix. Moreover, TIMP-1 displays anti-apoptotic properties, in patients with hepatocellular carcinoma (HCC) TIMP-1 serum levels are elevated and high TIMP-1 expression levels in HCC are associated with a poor prognosis. Therefore, TIMP-1 could functionally link fibrogenesis and carcinogenesis in the liver. The aim of our study was to characterize the role of TIMP-1 in hepatic fibrogenesis and carcinogenesis. Experimental hepatic fibrogenesis as well as diethylnitrosamine (DEN)\u00a0-induced hepatocarcinogenesis were studied in TIMP-1-deficient mice and wild type littermates. Hepatic TIMP-1 expression was upregulated following induction of liver fibrosis by bile duct ligation (BDL) or by carbon tetrachloride (CCl<jats:sub>4<\/jats:sub>). Unexpectedly, in comparison to wild type littermates, TIMP-1-deficient mice were not protected from liver fibrosis induced by BDL or CCl<jats:sub>4<\/jats:sub>. TIMP-1 expression was significantly higher in HCC nodules than in surrounding liver tissue. However, experimental hepatic carcinogenesis was similar in TIMP-1-deficient mice and wild type littermates following DEN-treatment or combined treatment with DEN and CCl<jats:sub>4<\/jats:sub>. Therefore we concluded that TIMP-1 is not essential for hepatic fibrogenesis and carcinogenesis in mice.<\/jats:p>","DOI":"10.1038\/s41598-017-00671-1","type":"journal-article","created":{"date-parts":[[2017,3,31]],"date-time":"2017-03-31T15:31:24Z","timestamp":1490974284000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":68,"title":["TIMP-1 is upregulated, but not essential in hepatic fibrogenesis and carcinogenesis in mice"],"prefix":"10.1038","volume":"7","author":[{"given":"Nina D.","family":"Thiele","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jan W.","family":"Wirth","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David","family":"Steins","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anja C.","family":"Koop","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Harald","family":"Ittrich","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ansgar W.","family":"Lohse","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Johannes","family":"Kluwe","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2017,4,6]]},"reference":[{"key":"671_CR1","doi-asserted-by":"publisher","first-page":"S35","DOI":"10.1053\/j.gastro.2004.09.014","volume":"127","author":"G Fattovich","year":"2004","unstructured":"Fattovich, G., Stroffolini, T., Zagni, I. & Donato, F. Hepatocellular carcinoma in cirrhosis: incidence and risk factors. Gastroenterology \n                           127, S35\u201350 (2004).","journal-title":"Gastroenterology"},{"key":"671_CR2","doi-asserted-by":"publisher","first-page":"143","DOI":"10.1055\/s-2005-871194","volume":"25","author":"M Sherman","year":"2005","unstructured":"Sherman, M. Hepatocellular carcinoma: epidemiology, risk factors, and screening. Semin Liver Dis \n                           25, 143\u2013154 (2005).","journal-title":"Semin Liver Dis"},{"key":"671_CR3","doi-asserted-by":"publisher","first-page":"955","DOI":"10.1016\/j.jhep.2007.02.003","volume":"46","author":"S Hemmann","year":"2007","unstructured":"Hemmann, S., Graf, J., Roderfeld, M. & Roeb, E. Expression of MMPs and TIMPs in liver fibrosis\u2013a systematic review with special emphasis on anti-fibrotic strategies. J Hepatol \n                           46, 955\u2013975 (2007).","journal-title":"J Hepatol"},{"key":"671_CR4","doi-asserted-by":"publisher","first-page":"1937","DOI":"10.1053\/j.gastro.2007.02.033","volume":"132","author":"S De Minicis","year":"2007","unstructured":"De Minicis, S. et al. Gene expression profiles during hepatic stellate cell activation in culture and in vivo. Gastroenterology \n                           132, 1937\u20131946 (2007).","journal-title":"Gastroenterology"},{"key":"671_CR5","first-page":"1647","volume":"150","author":"H Herbst","year":"1997","unstructured":"Herbst, H. et al. Tissue inhibitor of metalloproteinase-1 and -2 RNA expression in rat and human liver fibrosis. The American journal of pathology \n                           150, 1647\u20131659 (1997).","journal-title":"The American journal of pathology"},{"key":"671_CR6","doi-asserted-by":"publisher","first-page":"47","DOI":"10.1016\/0009-8981(93)90221-O","volume":"218","author":"Y Murawaki","year":"1993","unstructured":"Murawaki, Y., Yamamoto, H., Kawasaki, H. & Shima, H. Serum tissue inhibitor of metalloproteinases in patients with chronic liver disease and with hepatocellular carcinoma. Clin Chim Acta \n                           218, 47\u201358 (1993).","journal-title":"Clin Chim Acta"},{"key":"671_CR7","doi-asserted-by":"publisher","first-page":"821","DOI":"10.1053\/gast.1996.v110.pm8608892","volume":"110","author":"RC Benyon","year":"1996","unstructured":"Benyon, R. C., Iredale, J. P., Goddard, S., Winwood, P. J. & Arthur, M. J. Expression of tissue inhibitor of metalloproteinases 1 and 2 is increased in fibrotic human liver. Gastroenterology \n                           110, 821\u2013831 (1996).","journal-title":"Gastroenterology"},{"key":"671_CR8","doi-asserted-by":"publisher","first-page":"1260","DOI":"10.1136\/gut.2010.209551","volume":"60","author":"J Kluwe","year":"2011","unstructured":"Kluwe, J. et al. Absence of hepatic stellate cell retinoid lipid droplets does not enhance hepatic fibrosis but decreases hepatic carcinogenesis. Gut \n                           60, 1260\u20131268 (2011).","journal-title":"Gut"},{"key":"671_CR9","doi-asserted-by":"publisher","first-page":"236","DOI":"10.1016\/j.jhep.2013.03.016","volume":"59","author":"R Lichtinghagen","year":"2013","unstructured":"Lichtinghagen, R. et al. The Enhanced Liver Fibrosis (ELF) score: normal values, influence factors and proposed cut-off values. J Hepatol \n                           59, 236\u2013242 (2013).","journal-title":"J Hepatol"},{"key":"671_CR10","doi-asserted-by":"publisher","first-page":"1248","DOI":"10.1053\/jhep.2000.20521","volume":"32","author":"H Yoshiji","year":"2000","unstructured":"Yoshiji, H. et al. Tissue inhibitor of metalloproteinases-1 promotes liver fibrosis development in a transgenic mouse model. Hepatology \n                           32, 1248\u20131254 (2000).","journal-title":"Hepatology"},{"key":"671_CR11","doi-asserted-by":"publisher","first-page":"850","DOI":"10.1053\/jhep.2002.35625","volume":"36","author":"H Yoshiji","year":"2002","unstructured":"Yoshiji, H. et al. Tissue inhibitor of metalloproteinases-1 attenuates spontaneous liver fibrosis resolution in the transgenic mouse. Hepatology \n                           36, 850\u2013860 (2002).","journal-title":"Hepatology"},{"key":"671_CR12","doi-asserted-by":"publisher","first-page":"444","DOI":"10.1096\/fj.05-4828com","volume":"20","author":"M Roderfeld","year":"2006","unstructured":"Roderfeld, M. et al. Inhibition of hepatic fibrogenesis by matrix metalloproteinase-9 mutants in mice. FASEB J \n                           20, 444\u2013454 (2006).","journal-title":"FASEB J"},{"key":"671_CR13","doi-asserted-by":"crossref","unstructured":"Parsons, C. J. et al. Antifibrotic effects of a tissue inhibitor of metalloproteinase-1 antibody on established liver fibrosis in rats. Hepatology \n                           40 (2004).","DOI":"10.1002\/hep.20425"},{"key":"671_CR14","doi-asserted-by":"publisher","first-page":"14","DOI":"10.1186\/2045-3701-1-14","volume":"1","author":"H Wang","year":"2011","unstructured":"Wang, H. et al. Tissue inhibitor of metalloproteinase 1 (TIMP-1) deficiency exacerbates carbon tetrachloride-induced liver injury and fibrosis in mice: involvement of hepatocyte STAT3 in TIMP-1 production. Cell Biosci \n                           1, 14 (2011).","journal-title":"Cell Biosci"},{"key":"671_CR15","doi-asserted-by":"publisher","first-page":"11069","DOI":"10.1074\/jbc.M111490200","volume":"277","author":"FR Murphy","year":"2002","unstructured":"Murphy, F. R. et al. Inhibition of apoptosis of activated hepatic stellate cells by tissue inhibitor of metalloproteinase-1 is mediated via effects on matrix metalloproteinase inhibition: implications for reversibility of liver fibrosis. J Biol Chem \n                           277, 11069\u201311076 (2002).","journal-title":"J Biol Chem"},{"key":"671_CR16","doi-asserted-by":"publisher","first-page":"479","DOI":"10.1023\/A:1012493808790","volume":"6","author":"F Mannello","year":"2001","unstructured":"Mannello, F. & Gazzanelli, G. Tissue inhibitors of metalloproteinases and programmed cell death: conundrums, controversies and potential implications. Apoptosis \n                           6, 479\u2013482 (2001).","journal-title":"Apoptosis"},{"key":"671_CR17","doi-asserted-by":"publisher","first-page":"e0137673","DOI":"10.1371\/journal.pone.0137673","volume":"10","author":"S Nalluri","year":"2015","unstructured":"Nalluri, S. et al. TIMP-1 Inhibits Apoptosis in Lung Adenocarcinoma Cells via Interaction with Bcl-2. PLoS One \n                           10, e0137673 (2015).","journal-title":"PLoS One"},{"key":"671_CR18","doi-asserted-by":"publisher","first-page":"81","DOI":"10.1002\/(SICI)1097-0215(19980105)75:1<81::AID-IJC13>3.0.CO;2-G","volume":"75","author":"H Yoshiji","year":"1998","unstructured":"Yoshiji, H. et al. Mammary carcinoma cells over-expressing tissue inhibitor of metalloproteinases-1 show enhanced vascular endothelial growth factor expression. Int J Cancer \n                           75, 81\u201387 (1998).","journal-title":"Int J Cancer"},{"key":"671_CR19","first-page":"87","volume":"16","author":"E Yamada","year":"2001","unstructured":"Yamada, E. et al. TIMP-1 promotes VEGF-induced neovascularization in the retina. Histol Histopathol \n                           16, 87\u201397 (2001).","journal-title":"Histol Histopathol"},{"key":"671_CR20","doi-asserted-by":"publisher","first-page":"2050","DOI":"10.1002\/ijc.23337","volume":"122","author":"ZS Wu","year":"2008","unstructured":"Wu, Z. S. et al. Prognostic significance of MMP-9 and TIMP-1 serum and tissue expression in breast cancer. Int J Cancer \n                           122, 2050\u20132056 (2008).","journal-title":"Int J Cancer"},{"key":"671_CR21","doi-asserted-by":"publisher","first-page":"899","DOI":"10.3109\/00365521.2013.812235","volume":"48","author":"M Grunnet","year":"2013","unstructured":"Grunnet, M., Mau-Sorensen, M. & Brunner, N. Tissue inhibitor of metalloproteinase 1 (TIMP-1) as a biomarker in gastric cancer: a review. Scand J Gastroenterol \n                           48, 899\u2013905 (2013).","journal-title":"Scand J Gastroenterol"},{"key":"671_CR22","doi-asserted-by":"publisher","first-page":"205","DOI":"10.1159\/000112827","volume":"72","author":"N Yukawa","year":"2007","unstructured":"Yukawa, N. et al. Impact of plasma tissue inhibitor of matrix metalloproteinase-1 on long-term survival in patients with colorectal cancer. Oncology \n                           72, 205\u2013208 (2007).","journal-title":"Oncology"},{"key":"671_CR23","doi-asserted-by":"crossref","unstructured":"Rauvala, M., Puistola, U. & Turpeenniemi-Hujanen, T. Gelatinases and their tissue inhibitors in ovarian tumors; TIMP-1 is a predictive as well as a prognostic factor. Gynecol Oncol \n                           99 (2005).","DOI":"10.1016\/j.ygyno.2005.07.009"},{"key":"671_CR24","first-page":"1311","volume":"20","author":"S Ylisirnio","year":"2000","unstructured":"Ylisirnio, S., Hoyhtya, M. & Turpeenniemi-Hujanen, T. Serum matrix metalloproteinases -2, -9 and tissue inhibitors of metalloproteinases -1, -2 in lung cancer\u2013TIMP-1 as a prognostic marker. Anticancer Res \n                           20, 1311\u20131316 (2000).","journal-title":"Anticancer Res"},{"key":"671_CR25","doi-asserted-by":"publisher","first-page":"437","DOI":"10.1111\/j.1440-1746.1993.tb01544.x","volume":"8","author":"DA Muzzillo","year":"1993","unstructured":"Muzzillo, D. A. et al. Clinical evaluation of serum tissue inhibitor of metalloproteinases-1 levels in patients with liver diseases. J Gastroenterol Hepatol \n                           8, 437\u2013441 (1993).","journal-title":"J Gastroenterol Hepatol"},{"key":"671_CR26","doi-asserted-by":"publisher","first-page":"12061","DOI":"10.18632\/oncotarget.3616","volume":"6","author":"T Song","year":"2015","unstructured":"Song, T., Dou, C., Jia, Y., Tu, K. & Zheng, X. TIMP-1 activated carcinoma-associated fibroblasts inhibit tumor apoptosis by activating SDF1\/CXCR4 signaling in hepatocellular carcinoma. Oncotarget \n                           6, 12061\u201312079 (2015).","journal-title":"Oncotarget"},{"key":"671_CR27","doi-asserted-by":"publisher","first-page":"2245","DOI":"10.1038\/sj.onc.1205291","volume":"21","author":"Y Jiang","year":"2002","unstructured":"Jiang, Y., Goldberg, I. D. & Shi, Y. E. Complex roles of tissue inhibitors of metalloproteinases in cancer. Oncogene \n                           21, 2245\u20132252 (2002).","journal-title":"Oncogene"},{"key":"671_CR28","doi-asserted-by":"publisher","first-page":"8615","DOI":"10.1158\/0008-5472.CAN-07-0232","volume":"67","author":"C Kopitz","year":"2007","unstructured":"Kopitz, C. et al. Tissue inhibitor of metalloproteinases-1 promotes liver metastasis by induction of hepatocyte growth factor signaling. Cancer Res \n                           67, 8615\u20138623 (2007).","journal-title":"Cancer Res"},{"key":"671_CR29","first-page":"2307","volume":"13","author":"PD Soloway","year":"1996","unstructured":"Soloway, P. D., Alexander, C. M., Werb, Z. & Jaenisch, R. Targeted mutagenesis of Timp-1 reveals that lung tumor invasion is influenced by Timp-1 genotype of the tumor but not by that of the host. Oncogene \n                           13, 2307\u20132314 (1996).","journal-title":"Oncogene"},{"key":"671_CR30","doi-asserted-by":"publisher","first-page":"238","DOI":"10.1002\/hep.27378","volume":"61","author":"B Seubert","year":"2015","unstructured":"Seubert, B. et al. Tissue inhibitor of metalloproteinases (TIMP)-1 creates a premetastatic niche in the liver through SDF-1\/CXCR4-dependent neutrophil recruitment in mice. Hepatology \n                           61, 238\u2013248 (2015).","journal-title":"Hepatology"},{"key":"671_CR31","doi-asserted-by":"publisher","first-page":"379","DOI":"10.1111\/j.1478-3231.2004.0923.x","volume":"24","author":"E Matsumoto","year":"2004","unstructured":"Matsumoto, E. et al. Increased levels of tissue inhibitor of metalloproteinase-1 in human hepatocellular carcinoma. Liver Int \n                           24, 379\u2013383 (2004).","journal-title":"Liver Int"},{"key":"671_CR32","doi-asserted-by":"publisher","first-page":"347","DOI":"10.1053\/j.gastro.2009.09.015","volume":"138","author":"J Kluwe","year":"2010","unstructured":"Kluwe, J. et al. Modulation of hepatic fibrosis by c-Jun-N-terminal kinase inhibition. Gastroenterology \n                           138, 347\u2013359 (2010).","journal-title":"Gastroenterology"},{"key":"671_CR33","doi-asserted-by":"publisher","first-page":"977","DOI":"10.1016\/j.cell.2005.04.014","volume":"121","author":"S Maeda","year":"2005","unstructured":"Maeda, S., Kamata, H., Luo, J. L., Leffert, H. & Karin, M. IKK beta couples hepatocyte death to cytokine-driven compensatory proliferation that promotes chemical hepatocarcinogenesis. Cell \n                           121, 977\u2013990 (2005).","journal-title":"Cell"},{"key":"671_CR34","doi-asserted-by":"publisher","first-page":"680","DOI":"10.1038\/227680a0","volume":"227","author":"UK Laemmli","year":"1970","unstructured":"Laemmli, U. K. Cleavage of structural proteins during the assembly of the head of bacteriophage T4. Nature \n                           227, 680\u2013685 (1970).","journal-title":"Nature"},{"key":"671_CR35","doi-asserted-by":"crossref","unstructured":"Hiroshi Uchinami, Ekihiro Seki, David A. Brenner & Jeanine D\u2019Armiento. Loss of MMP 13 attenuates murine hepatic injury and fibrosis during cholestasis. Hepatology \n                           44 (2), 420\u20139 (2006).","DOI":"10.1002\/hep.21268"}],"container-title":["Scientific Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41598-017-00671-1.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-017-00671-1","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-017-00671-1.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,12,23]],"date-time":"2022-12-23T03:35:14Z","timestamp":1671766514000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41598-017-00671-1"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2017,4,6]]},"references-count":35,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2017,12]]}},"alternative-id":["671"],"URL":"https:\/\/doi.org\/10.1038\/s41598-017-00671-1","relation":{},"ISSN":["2045-2322"],"issn-type":[{"value":"2045-2322","type":"electronic"}],"subject":[],"published":{"date-parts":[[2017,4,6]]},"assertion":[{"value":"19 December 2016","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"8 March 2017","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"6 April 2017","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare that they have no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing Interests"}}],"article-number":"714"}}