{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,14]],"date-time":"2026-01-14T23:54:57Z","timestamp":1768434897117,"version":"3.49.0"},"reference-count":25,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"3","license":[{"start":{"date-parts":[[2015,9,1]],"date-time":"2015-09-01T00:00:00Z","timestamp":1441065600000},"content-version":"tdm","delay-in-days":1460,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["lww.com","ovid.com"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2011,9,2]]},"abstract":"<jats:sec>\n            <jats:title\/>\n            <jats:p>\n                                 <jats:bold>Cholangiocarcinoma (CCA) carries a severe prognosis because of its strong invasiveness and early metastasization. In several patients, otherwise eligible for surgical resection, micrometastasis are already present at the time of surgery. The mechanisms responsible for CCA invasiveness are unclear. S100A4, a member of the S100 family of small Ca2+-binding proteins, is expressed in mesenchymal cells, regulates cell motility in several cell types, and is expressed in some epithelial cancers. Thus, we aimed to study the role of S100A4 in CCA invasiveness and metastasization. The expression of S100A4 was studied by immunohistochemistry in 93 human liver samples of CCA patients undergoing surgical resection and correlated with metastases development (67 cases) and patient survival following surgery using log rank tests and multivariate analysis. S100A4 expression was studied in EGI-1 and TFK-1, human CCA cell lines with and without nuclear S100A4 expression, respectively. Metastatic properties of CCA cells were assessed by xenotransplantation in severe combined immunodeficiency (SCID) mice after transduction with lentiviral vectors encoding firefly luciferase gene. Proliferation, motility (wound healing), invasiveness (Boyden chamber), and metalloproteinases (MMPs) secretion were studied in CCA cells, with or without lentiviral silencing of S100A4. Nuclear expression of S100A4 by neoplastic ducts was a strong predictor of metastasization and reduced survival after resection<\/jats:bold>\n                                 <jats:bold>\n                                    (P\n                                 <\/jats:bold>\n                                 <jats:bold>&lt; 0.01). EGI-1 CCA cells showed stronger metastatic properties than TFK-1 when xenotransplanted in SCID mice. S100A4-silenced EGI-1 cells showed significantly reduced motility, invasiveness, and MMP-9 secretion<\/jats:bold>\n                                 <jats:bold>\n                                    in vitro,\n                                 <\/jats:bold>\n                                 <jats:bold>without changes in cell proliferation.<\/jats:bold>\n                                 <jats:bold>\n                                    Conclusion:\n                                 <\/jats:bold>\n                                 <jats:bold>Nuclear S100A4 identifies a subset of CCA patients with a poor prognosis after surgical resection. Nuclear expression of S100A4 increases CCA cells invasiveness and metastasization, indicating that S100A4 may also represent a potential therapeutic target. (HEPATOLOGY 2011; 54:890\u2013899)<\/jats:bold>\n                              <\/jats:p>\n          <\/jats:sec>","DOI":"10.1002\/hep.24466","type":"journal-article","created":{"date-parts":[[2011,5,26]],"date-time":"2011-05-26T14:48:31Z","timestamp":1306421311000},"page":"890-899","update-policy":"https:\/\/doi.org\/10.1097\/lww.0000000000001000","source":"Crossref","is-referenced-by-count":77,"title":["Nuclear expression of S100A4 calcium-binding protein increases cholangiocarcinoma invasiveness and metastasization"],"prefix":"10.1097","volume":"54","author":[{"given":"Luca","family":"Fabris","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Massimiliano","family":"Cadamuro","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lidia","family":"Moserle","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"James","family":"Dziura","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xiangyu","family":"Cong","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Luisa","family":"Sambado","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Giorgia","family":"Nardo","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Aurelio","family":"Sonzogni","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Michele","family":"Colledan","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alberto","family":"Furlanetto","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nicol\u00f2","family":"Bassi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marco","family":"Massani","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Umberto","family":"Cillo","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Claudia","family":"Mescoli","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Stefano","family":"Indraccolo","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Massimo","family":"Rugge","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lajos","family":"Okolicsanyi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mario","family":"Strazzabosco","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"276","reference":[{"key":"R1-17-20241201","doi-asserted-by":"crossref","first-page":"308321","DOI":"10.1002\/hep.22310","article-title":"Cholangiocarcinoma: advances in pathogenesis, diagnosis, and treatment.","volume":"48","author":"Blechacz","year":"2008","journal-title":"HEPATOLOGY"},{"key":"R2-17-20241201","doi-asserted-by":"crossref","first-page":"12731281","DOI":"10.1056\/NEJMoa0908721","article-title":"Cisplatin plus gemcitabine versus gemcitabine for biliary tract cancer.","volume":"362","author":"Valle","year":"2010","journal-title":"N Engl J Med"},{"key":"R3-17-20241201","doi-asserted-by":"crossref","first-page":"442454","DOI":"10.1038\/nrc822","article-title":"Epithelialmesenchymal transitions in tumour progression.","volume":"2","author":"Thiery","year":"2002","journal-title":"Nat Rev Cancer"},{"key":"R4-17-20241201","doi-asserted-by":"crossref","first-page":"14291437","DOI":"10.1172\/JCI36183","article-title":"Biomarkers for epithelialmesenchymal transitions.","volume":"119","author":"Zeisberg","year":"2009","journal-title":"J Clin Invest"},{"key":"R5-17-20241201","doi-asserted-by":"crossref","first-page":"308313","DOI":"10.1073\/pnas.1017547108","article-title":"Fibroblastspecific protein 1 identifies an inflammatory subpopulation of macrophages in the liver.","volume":"108","author":"Osterreicher","year":"2011","journal-title":"Proc Natl Acad Sci U S A"},{"key":"R6-17-20241201","doi-asserted-by":"crossref","first-page":"528535","DOI":"10.2353\/ajpath.2010.090526","article-title":"S100A4 and metastasis: a small actor playing many roles.","volume":"176","author":"Boye","year":"2010","journal-title":"Am J Pathol"},{"key":"R7-17-20241201","doi-asserted-by":"crossref","first-page":"14781484","DOI":"10.1053\/gast.2002.36606","article-title":"Prognostic significance of calciumbinding protein S100A4 in colorectal cancer.","volume":"123","author":"Gongoll","year":"2002","journal-title":"Gastroenterology"},{"key":"R8-17-20241201","doi-asserted-by":"crossref","first-page":"1482514830","DOI":"10.1073\/pnas.0606747103","article-title":"S100A4 accelerates tumorigenesis and invasion of human prostate cancer through the transcriptional regulation of matrix metalloproteinase 9.","volume":"103","author":"Saleem","year":"2006","journal-title":"Proc Natl Acad Sci U S A"},{"key":"R9-17-20241201","doi-asserted-by":"crossref","first-page":"211218","DOI":"10.1016\/j.canlet.2004.12.046","article-title":"S100A4 regulates Ecadherin expression in oral squamous cell carcinoma.","volume":"230","author":"MoriyamaKita","year":"2005","journal-title":"Cancer Lett"},{"key":"R10-17-20241201","doi-asserted-by":"crossref","first-page":"4957","DOI":"10.1111\/j.1467-9469.2005.00414.x","article-title":"Generalized logrank tests for intervalcensored failure time data.","volume":"32","author":"Sun","year":"2005","journal-title":"Scand J Stat"},{"key":"R11-17-20241201","doi-asserted-by":"crossref","first-page":"15831590","DOI":"10.3748\/wjg.v12.i10.1583","article-title":"Expression of ckit receptor in human cholangiocarcinoma and in vivo treatment with imatinib mesilate in chimeric mice.","volume":"12","author":"Kamenz","year":"2006","journal-title":"World J Gastroenterol"},{"key":"R12-17-20241201","doi-asserted-by":"crossref","first-page":"141152","DOI":"10.2353\/ajpath.2010.090747","article-title":"Epithelialmesenchymal transition induced by transforming growth factorbeta1snail activation aggravates invasive growth of cholangiocarcinoma.","volume":"177","author":"Sato","year":"2010","journal-title":"Am J Pathol"},{"key":"R13-17-20241201","doi-asserted-by":"crossref","first-page":"9991007","DOI":"10.1007\/s00259-007-0664-2","article-title":"Dynamic bioluminescence imaging for quantitative tumour burden assessment using IV or IP administration of Dluciferin: effect on intensity, time kinetics and repeatability of photon emission.","volume":"35","author":"Keyaerts","year":"2008","journal-title":"Eur J Nucl Med Mol Imaging"},{"key":"R14-17-20241201","doi-asserted-by":"crossref","first-page":"957970","DOI":"10.1089\/hum.2005.16.957","article-title":"Interferonalpha gene therapy by lentiviral vectors contrasts ovarian cancer growth through angiogenesis inhibition.","volume":"16","author":"Indraccolo","year":"2005","journal-title":"Hum Gene Ther"},{"key":"R15-17-20241201","first-page":"60996107","article-title":"Gene transfer in ovarian cancer cells: a comparison between retroviral and lentiviral vectors.","volume":"62","author":"Indraccolo","year":"2002","journal-title":"Cancer Res"},{"key":"R16-17-20241201","doi-asserted-by":"crossref","first-page":"329333","DOI":"10.1038\/nprot.2007.30","article-title":"In vitro scratch assay: a convenient and inexpensive method for analysis of cell migration in vitro.","volume":"2","author":"Liang","year":"2007","journal-title":"Nat Protoc"},{"key":"R17-17-20241201","doi-asserted-by":"crossref","first-page":"22672278","DOI":"10.1093\/carcin\/bgn216","article-title":"Redox mechanisms switch on hypoxiadependent epithelialmesenchymal transition in cancer cells.","volume":"29","author":"Cannito","year":"2008","journal-title":"Carcinogenesis"},{"key":"R18-17-20241201","doi-asserted-by":"crossref","first-page":"10011012","DOI":"10.1002\/hep.21143","article-title":"Effects of angiogenic factor overexpression by human and rodent cholangiocytes in polycystic liver diseases.","volume":"43","author":"Fabris","year":"2006","journal-title":"HEPATOLOGY"},{"key":"R19-17-20241201","first-page":"15951603","article-title":"Prognostic significance of the metastasisinducing protein S100A4 (p9Ka) in human breast cancer.","volume":"60","author":"Rudland","year":"2000","journal-title":"Cancer Res"},{"key":"R20-17-20241201","doi-asserted-by":"crossref","first-page":"589595","DOI":"10.1002\/path.1381","article-title":"Nuclear localization of the metastasisrelated protein S100A4 correlates with tumour stage in colorectal cancer.","volume":"200","author":"Flatmark","year":"2003","journal-title":"J Pathol"},{"key":"R21-17-20241201","first-page":"108115","article-title":"Insulin resistance and necroinflammation drives ductular reaction and epithelialmesenchymal transition in chronic hepatitis C.","volume":"60","author":"SvegliatiBaroni","year":"2010","journal-title":"Gut"},{"key":"R22-17-20241201","first-page":"220232","article-title":"Calciumdependent translocation of S100A11 requires tubulin filaments.","volume":"1498","author":"Davey","year":"2000","journal-title":"Biochim Biophys Acta"},{"key":"R23-17-20241201","doi-asserted-by":"crossref","first-page":"78347846","DOI":"10.1021\/bi00024a007","article-title":"Interactions of myogenic bHLH transcription factors with calciumbinding calmodulin and S100a (alpha alpha) proteins.","volume":"34","author":"Baudier","year":"1995","journal-title":"Biochemistry"},{"key":"R24-17-20241201","doi-asserted-by":"crossref","first-page":"2393023937","DOI":"10.1074\/jbc.272.38.23930","article-title":"Basic helixloophelix protein sequences determining differential inhibition by calmodulin and S100 proteins.","volume":"272","author":"Onions","year":"1997","journal-title":"J Biol Chem"},{"key":"R25-17-20241201","first-page":"62","article-title":"Taxol, a promoter of microtubule polymerisation, down regulates metastasis associated mts1 gene in the B16 murine melanoma.","volume":"34","author":"Parker","year":"1993","journal-title":"Proc Am Assoc Cancer Res"}],"container-title":["Hepatology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1002%2Fhep.24466","content-type":"unspecified","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/journals.lww.com\/01515467-201109020-00017","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,12,1]],"date-time":"2024-12-01T13:49:24Z","timestamp":1733060964000},"score":1,"resource":{"primary":{"URL":"https:\/\/journals.lww.com\/01515467-201109020-00017"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2011,9,2]]},"references-count":25,"journal-issue":{"issue":"3","published-print":{"date-parts":[[2011]]}},"URL":"https:\/\/doi.org\/10.1002\/hep.24466","relation":{},"ISSN":["0270-9139"],"issn-type":[{"value":"0270-9139","type":"print"}],"subject":[],"published":{"date-parts":[[2011,9,2]]}}}