{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,23]],"date-time":"2026-09-23T21:00:13Z","timestamp":1790197213163,"version":"4.1.0"},"reference-count":48,"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":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["lww.com","ovid.com"],"crossmark-restriction":true},"short-container-title":["Hepatology"],"published-print":{"date-parts":[[2016,9]]},"abstract":"<jats:p>Several chronic inflammatory liver diseases, e.g., chronic hepatitis B or C viral infection and steatohepatitis, have been shown to predispose to the development of hepatocellular carcinoma (HCC). In patients with chronic liver disease, interleukin\u20106 (IL\u20106) serum levels are elevated and increase even more when HCC develops. However, the impact and regulatory mechanisms of IL\u20106 signaling during hepatocarcinogenesis are still poorly defined. Here, we show that gene expression profiles of patients with chromosome 8p loss correlate with increased IL\u20106 signaling. In addition, the chromosome 8p tumor suppressor genes Src homology 2 domain containing 4A (SH2D4A) and Sorbin and Src homology 3 domain containing 3 (SORBS3) together exerted greater inhibition of cell growth and clonogenicity compared to a single gene. Overexpression of SH2D4A and SORBS3 in HCC cells led to decreased IL\u20106 target gene expression and reduced signal transducer and activator of transcription 3 (STAT3) signaling. <jats:italic toggle=\"yes\">In situ<\/jats:italic> and <jats:italic toggle=\"yes\">in vitro<\/jats:italic> coimmunoprecipitation assays revealed that SH2D4A directly interacts with STAT3, thereby retaining STAT3 in the cytoplasm and inhibiting STAT3 transcriptional activity. On the other hand, SORBS3 coactivated estrogen receptor \u03b1 signaling, leading indirectly to repression of STAT3 signaling. In human HCC tissues, SH2D4A was positively associated with infiltrating regulatory and cytotoxic T\u2010cell populations, suggesting distinct immunophenotypes in HCC subgroups with chromosome 8p loss. Thus, the genetically linked tumor suppressors SH2D4A and SORBS3 functionally cooperate to inhibit STAT3 signaling in HCC. <jats:italic toggle=\"yes\">Conclusion:<\/jats:italic> The chromosome 8p tumor suppressor genes SORBS3 and SH2D4A are physically and functionally linked and provide a molecular mechanism of inhibiting STAT3\u2010mediated IL\u20106 signaling in HCC cells. (H<jats:sc>epatology<\/jats:sc> 2016;64:828\u2010842)<\/jats:p>","DOI":"10.1002\/hep.28684","type":"journal-article","created":{"date-parts":[[2016,6,17]],"date-time":"2016-06-17T01:23:34Z","timestamp":1466126614000},"page":"828-842","update-policy":"https:\/\/doi.org\/10.1097\/lww.0000000000001000","source":"Crossref","is-referenced-by-count":39,"title":["Chromosome 8p tumor suppressor genes SH2D4A and SORBS3 cooperate to inhibit interleukin\u20106 signaling in hepatocellular carcinoma"],"prefix":"10.1097","volume":"64","author":[{"given":"Carolin","family":"Ploeger","sequence":"first","affiliation":[{"name":"Department of General Pathology, Institute of Pathology,University Hospital Heidelberg,Heidelberg,Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nina","family":"Waldburger","sequence":"additional","affiliation":[{"name":"Department of General Pathology, Institute of Pathology,University Hospital Heidelberg,Heidelberg,Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Angelika","family":"Fraas","sequence":"additional","affiliation":[{"name":"Department of General Pathology, Institute of Pathology,University Hospital Heidelberg,Heidelberg,Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Benjamin","family":"Goeppert","sequence":"additional","affiliation":[{"name":"Department of General Pathology, Institute of Pathology,University Hospital Heidelberg,Heidelberg,Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stefan","family":"Pusch","sequence":"additional","affiliation":[{"name":"Department of Neuropathology, Institute of Pathology,University Hospital Heidelberg,Heidelberg,Germany"},{"name":"Clinical Cooperation Unit Neuropathology,German Cancer Research Center,Heidelberg,Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kai","family":"Breuhahn","sequence":"additional","affiliation":[{"name":"Department of General Pathology, Institute of Pathology,University Hospital Heidelberg,Heidelberg,Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xin Wei","family":"Wang","sequence":"additional","affiliation":[{"name":"Laboratory of Human Carcinogenesis, National Cancer Institute,National Institutes of Health,Bethesda,MD"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter","family":"Schirmacher","sequence":"additional","affiliation":[{"name":"Department of General Pathology, Institute of Pathology,University Hospital Heidelberg,Heidelberg,Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephanie","family":"Roessler","sequence":"additional","affiliation":[{"name":"Department of General Pathology, Institute of Pathology,University Hospital Heidelberg,Heidelberg,Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","published-online":{"date-parts":[[2016,7,15]]},"reference":[{"key":"hep28684-bib-0001-20241017","doi-asserted-by":"crossref","first-page":"69","DOI":"10.3322\/caac.20107","article-title":"Global cancer statistics","volume":"61","year":"2011","journal-title":"CA Cancer J Clin"},{"key":"hep28684-bib-0002-20241017","doi-asserted-by":"crossref","first-page":"2913","DOI":"10.1158\/0008-5472.CAN-14-0155","article-title":"Projecting cancer incidence and deaths to 2030: the unexpected burden of thyroid, liver, and pancreas cancers in the United States","volume":"74","year":"2014","journal-title":"Cancer Res"},{"key":"hep28684-bib-0003-20241017","doi-asserted-by":"crossref","first-page":"883","DOI":"10.1016\/j.cell.2010.01.025","article-title":"Immunity, inflammation, and cancer","volume":"140","year":"2010","journal-title":"Cell"},{"key":"hep28684-bib-0004-20241017","doi-asserted-by":"crossref","first-page":"339","DOI":"10.1038\/ng0802-339","article-title":"Molecular pathogenesis of human hepatocellular carcinoma","volume":"31","year":"2002","journal-title":"Nat Genet"},{"key":"hep28684-bib-0005-20241017","doi-asserted-by":"crossref","first-page":"298","DOI":"10.1038\/nrc3245","article-title":"The immune contexture in human tumours: impact on clinical outcome","volume":"12","year":"2012","journal-title":"Nat Rev Cancer"},{"key":"hep28684-bib-0006-20241017","doi-asserted-by":"crossref","first-page":"1565","DOI":"10.1126\/science.1203486","article-title":"Cancer immunoediting: integrating immunity's roles in cancer suppression and promotion","volume":"331","year":"2011","journal-title":"Science"},{"key":"hep28684-bib-0007-20241017","doi-asserted-by":"crossref","first-page":"239","DOI":"10.1038\/nrc2618","article-title":"Microenvironmental regulation of metastasis","volume":"9","year":"2009","journal-title":"Nat Rev Cancer"},{"key":"hep28684-bib-0008-20241017","doi-asserted-by":"crossref","first-page":"539","DOI":"10.1016\/S0140-6736(00)04046-0","article-title":"Inflammation and cancer: back to Virchow?","volume":"357","year":"2001","journal-title":"Lancet"},{"key":"hep28684-bib-0009-20241017","doi-asserted-by":"crossref","first-page":"1423","DOI":"10.1038\/nm.3394","article-title":"Microenvironmental regulation of tumor progression and metastasis","volume":"19","year":"2013","journal-title":"Nat Med"},{"key":"hep28684-bib-0010-20241017","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1016\/j.ccr.2007.12.020","article-title":"Autocrine IL\u20106 signaling: a key event in tumorigenesis?","volume":"13","year":"2008","journal-title":"Cancer Cell"},{"key":"hep28684-bib-0011-20241017","doi-asserted-by":"crossref","first-page":"2264","DOI":"10.1002\/ijc.24720","article-title":"Serum IL\u20106 levels and the risk for hepatocarcinogenesis in chronic hepatitis C patients: an analysis based on gender differences","volume":"125","year":"2009","journal-title":"Int J Cancer"},{"key":"hep28684-bib-0012-20241017","doi-asserted-by":"crossref","first-page":"2766","DOI":"10.1002\/ijc.24281","article-title":"High serum interleukin\u20106 level predicts future hepatocellular carcinoma development in patients with chronic hepatitis B","volume":"124","year":"2009","journal-title":"Int J Cancer"},{"key":"hep28684-bib-0013-20241017","doi-asserted-by":"crossref","first-page":"1437","DOI":"10.1056\/NEJMoa0901282","article-title":"MicroRNA expression, survival, and response to interferon in liver cancer","volume":"361","year":"2009","journal-title":"N Engl J Med"},{"key":"hep28684-bib-0014-20241017","doi-asserted-by":"crossref","first-page":"121","DOI":"10.1126\/science.1140485","article-title":"Gender disparity in liver cancer due to sex differences in MyD88\u2010dependent IL\u20106 production","volume":"317","year":"2007","journal-title":"Science"},{"key":"hep28684-bib-0015-20241017","doi-asserted-by":"crossref","first-page":"1267","DOI":"10.1038\/ng.3126","article-title":"Trans\u2010ancestry mutational landscape of hepatocellular carcinoma genomes","volume":"46","year":"2014","journal-title":"Nat Genet"},{"key":"hep28684-bib-0016-20241017","doi-asserted-by":"crossref","first-page":"846","DOI":"10.1038\/nm.3915","article-title":"Toward understanding and exploiting tumor heterogeneity","volume":"21","year":"2015","journal-title":"Nat Med"},{"key":"hep28684-bib-0017-20241017","doi-asserted-by":"crossref","first-page":"104","DOI":"10.1126\/science.1219580","article-title":"Recurrent hemizygous deletions in cancers may optimize proliferative potential","volume":"337","year":"2012","journal-title":"Science"},{"key":"hep28684-bib-0018-20241017","doi-asserted-by":"crossref","first-page":"8212","DOI":"10.1073\/pnas.1206062109","article-title":"A cluster of cooperating tumor\u2010suppressor gene candidates in chromosomal deletions","volume":"109","year":"2012","journal-title":"Proc Natl Acad Sci USA"},{"key":"hep28684-bib-0019-20241017","doi-asserted-by":"crossref","first-page":"957","DOI":"10.1053\/j.gastro.2011.12.039","article-title":"Integrative genomic identification of genes on 8p associated with hepatocellular carcinoma progression and patient survival","volume":"142","year":"2012","journal-title":"Gastroenterology"},{"key":"hep28684-bib-0020-20241017","doi-asserted-by":"crossref","first-page":"10202","DOI":"10.1158\/0008-5472.CAN-10-2607","article-title":"A unique metastasis gene signature enables prediction of tumor relapse in early\u2010stage hepatocellular carcinoma patients","volume":"70","year":"2010","journal-title":"Cancer Res"},{"key":"hep28684-bib-0021-20241017","doi-asserted-by":"crossref","first-page":"516","DOI":"10.5483\/BMBRep.2009.42.8.516","article-title":"SH2D4A regulates cell proliferation via the ERalpha\/PLC\u2010gamma\/PKC pathway","volume":"42","year":"2009","journal-title":"BMB Rep"},{"key":"hep28684-bib-0022-20241017","doi-asserted-by":"crossref","first-page":"59","DOI":"10.1083\/jcb.144.1.59","article-title":"Vinexin: a novel vinculin\u2010binding protein with multiple SH3 domains enhances actin cytoskeletal organization","volume":"144","year":"1999","journal-title":"J Cell Biol"},{"key":"hep28684-bib-0023-20241017","doi-asserted-by":"crossref","first-page":"7122","DOI":"10.1038\/sj.onc.1210512","article-title":"Essential roles of ERK\u2010mediated phosphorylation of vinexin in cell spreading, migration and anchorage\u2010independent growth","volume":"26","year":"2007","journal-title":"Oncogene"},{"key":"hep28684-bib-0024-20241017","doi-asserted-by":"crossref","first-page":"200","DOI":"10.1038\/nature07475","article-title":"Frequent in\u2010frame somatic deletions activate gp130 in inflammatory hepatocellular tumours","volume":"457","year":"2009","journal-title":"Nature"},{"key":"hep28684-bib-0025-20241017","doi-asserted-by":"crossref","first-page":"736","DOI":"10.1038\/nrc3818","article-title":"Revisiting STAT3 signalling in cancer: new and unexpected biological functions","volume":"14","year":"2014","journal-title":"Nat Rev Cancer"},{"key":"hep28684-bib-0026-20241017","doi-asserted-by":"crossref","first-page":"3100","DOI":"10.1038\/onc.2010.63","article-title":"Protein kinase Cvarepsilon mediates Stat3Ser727 phosphorylation, Stat3\u2010regulated gene expression, and cell invasion in various human cancer cell lines through integration with MAPK cascade (RAF\u20101, MEK1\/2, and ERK1\/2)","volume":"29","year":"2010","journal-title":"Oncogene"},{"key":"hep28684-bib-0027-20241017","doi-asserted-by":"crossref","first-page":"7736","DOI":"10.1158\/0008-5472.CAN-08-1125","article-title":"Activation of signal transducer and activator of transcription 3 through a phosphomimetic serine 727 promotes prostate tumorigenesis independent of tyrosine 705 phosphorylation","volume":"68","year":"2008","journal-title":"Cancer Res"},{"key":"hep28684-bib-0028-20241017","doi-asserted-by":"crossref","first-page":"714","DOI":"10.1016\/j.ajpath.2011.05.005","article-title":"Hepatoprotective versus oncogenic functions of STAT3 in liver tumorigenesis","volume":"179","year":"2011","journal-title":"Am J Pathol"},{"key":"hep28684-bib-0029-20241017","doi-asserted-by":"crossref","first-page":"900","DOI":"10.1242\/jcs.072520","article-title":"The role of the N\u2010terminal domain in dimerization and nucleocytoplasmic shuttling of latent STAT3","volume":"124","year":"2011","journal-title":"J Cell Sci"},{"key":"hep28684-bib-0030-20241017","doi-asserted-by":"crossref","first-page":"34133","DOI":"10.1074\/jbc.M304531200","article-title":"STATs dimerize in the absence of phosphorylation","volume":"278","year":"2003","journal-title":"J Biol Chem"},{"key":"hep28684-bib-0031-20241017","doi-asserted-by":"crossref","first-page":"798","DOI":"10.1038\/nrc2734","article-title":"STATs in cancer inflammation and immunity: a leading role for STAT3","volume":"9","year":"2009","journal-title":"Nat Rev Cancer"},{"key":"hep28684-bib-0032-20241017","doi-asserted-by":"crossref","first-page":"9255","DOI":"10.1074\/jbc.M312160200","article-title":"The focal adhesion protein vinexin alpha regulates the phosphorylation and activity of estrogen receptor alpha","volume":"279","year":"2004","journal-title":"J Biol Chem"},{"key":"hep28684-bib-0033-20241017","doi-asserted-by":"crossref","first-page":"143","DOI":"10.1016\/S0014-5793(00)02296-1","article-title":"Cross\u2010talk between signal transducer and activator of transcription 3 and estrogen receptor signaling","volume":"486","year":"2000","journal-title":"FEBS Lett"},{"key":"hep28684-bib-0034-20241017","doi-asserted-by":"crossref","first-page":"48","DOI":"10.1038\/nm976","article-title":"Regulation of the innate and adaptive immune responses by Stat\u20103 signaling in tumor cells","volume":"10","year":"2004","journal-title":"Nat Med"},{"key":"hep28684-bib-0035-20241017","doi-asserted-by":"crossref","first-page":"79","DOI":"10.1016\/j.ccr.2009.01.009","article-title":"Inflammation and cancer: IL\u20106 and STAT3 complete the link","volume":"15","year":"2009","journal-title":"Cancer Cell"},{"key":"hep28684-bib-0036-20241017","doi-asserted-by":"crossref","first-page":"120","DOI":"10.1016\/j.jss.2010.10.030","article-title":"Activation of STAT3 signal pathway correlates with twist and E\u2010cadherin expression in hepatocellular carcinoma and their clinical significance","volume":"174","year":"2012","journal-title":"J Surg Res"},{"key":"hep28684-bib-0037-20241017","doi-asserted-by":"crossref","first-page":"6285","DOI":"10.1038\/ncomms7285","article-title":"Disruption of STAT3 signalling promotes KRAS\u2010induced lung tumorigenesis","volume":"6","year":"2015","journal-title":"Nat Commun"},{"key":"hep28684-bib-0038-20241017","doi-asserted-by":"crossref","first-page":"7736","DOI":"10.1038\/ncomms8736","article-title":"STAT3 regulated ARF expression suppresses prostate cancer metastasis","volume":"6","year":"2015","journal-title":"Nat Commun"},{"key":"hep28684-bib-0039-20241017","doi-asserted-by":"crossref","first-page":"12067","DOI":"10.1074\/jbc.M200018200","article-title":"Cytokine signaling: STATS in plasma membrane rafts","volume":"277","year":"2002","journal-title":"J Biol Chem"},{"key":"hep28684-bib-0040-20241017","doi-asserted-by":"crossref","first-page":"7302","DOI":"10.1074\/jbc.M508527200","article-title":"Membrane\u2010associated STAT3 and PY\u2010STAT3 in the cytoplasm","volume":"281","year":"2006","journal-title":"J Biol Chem"},{"key":"hep28684-bib-0041-20241017","doi-asserted-by":"crossref","first-page":"1248","DOI":"10.1158\/1078-0432.CCR-14-2291","article-title":"Interleukin\u20106 as a therapeutic target","volume":"21","year":"2015","journal-title":"Clin Cancer Res"},{"key":"hep28684-bib-0042-20241017","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1038\/nature14228","article-title":"A gp130\u2010Src\u2010YAP module links inflammation to epithelial regeneration","volume":"519","year":"2015","journal-title":"Nature"},{"key":"hep28684-bib-0043-20241017","doi-asserted-by":"crossref","first-page":"506","DOI":"10.1016\/j.jhep.2007.03.015","article-title":"Oral contraception and the risk of hepatocellular carcinoma","volume":"47","year":"2007","journal-title":"J Hepatol"},{"key":"hep28684-bib-0044-20241017","doi-asserted-by":"crossref","first-page":"31839","DOI":"10.1074\/jbc.M105185200","article-title":"Activation of estrogen receptor blocks interleukin\u20106\u2010inducible cell growth of human multiple myeloma involving molecular cross\u2010talk between estrogen receptor and STAT3 mediated by co\u2010regulator PIAS3","volume":"276","year":"2001","journal-title":"J Biol Chem"},{"key":"hep28684-bib-0045-20241017","doi-asserted-by":"crossref","first-page":"678","DOI":"10.1002\/hep.25980","article-title":"Estrogen\u2010sensitive PTPRO expression represses hepatocellular carcinoma progression by control of STAT3","volume":"57","year":"2013","journal-title":"Hepatology"},{"key":"hep28684-bib-0046-20241017","doi-asserted-by":"crossref","first-page":"1957","DOI":"10.1002\/hep.27728","article-title":"Tumor\u2010infiltrating, interleukin\u201033\u2010producing effector\u2010memory CD8+ T cells in resected hepatocellular carcinoma prolong patient survival","volume":"61","year":"2015","journal-title":"Hepatology"},{"key":"hep28684-bib-0047-20241017","doi-asserted-by":"crossref","first-page":"1232","DOI":"10.1002\/hep.26779","article-title":"Antitumor CD8+ T cells in hepatocellular carcinoma: present but exhausted","volume":"59","year":"2014","journal-title":"Hepatology"},{"key":"hep28684-bib-0048-20241017","doi-asserted-by":"crossref","first-page":"547","DOI":"10.1038\/nature10599","article-title":"Senescence surveillance of pre\u2010malignant hepatocytes limits liver cancer development","volume":"479","year":"2011","journal-title":"Nature"}],"container-title":["Hepatology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1002%2Fhep.28684","content-type":"unspecified","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/journals.lww.com\/01515467-201609000-00015","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,10,17]],"date-time":"2024-10-17T23:19:10Z","timestamp":1729207150000},"score":1,"resource":{"primary":{"URL":"https:\/\/journals.lww.com\/01515467-201609000-00015"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2016,7,15]]},"references-count":48,"journal-issue":{"issue":"3","published-print":{"date-parts":[[2016]]}},"URL":"https:\/\/doi.org\/10.1002\/hep.28684","relation":{},"ISSN":["0270-9139","1527-3350"],"issn-type":[{"value":"0270-9139","type":"print"},{"value":"1527-3350","type":"electronic"}],"subject":[],"published":{"date-parts":[[2016,7,15]]},"assertion":[{"value":"2016-01-11","name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2016-06-03","name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}}]}}