{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,23]],"date-time":"2026-09-23T01:54:59Z","timestamp":1790128499627,"version":"4.0.1"},"reference-count":35,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"1","license":[{"start":{"date-parts":[[2015,9,1]],"date-time":"2015-09-01T00:00:00Z","timestamp":1441065600000},"content-version":"tdm","delay-in-days":1339,"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":[[2012,1]]},"abstract":"<jats:sec>\n                    <jats:title\/>\n                    <jats:p>\n                      <jats:bold>Hepatitis B virus X (HBx) protein is implicated in hepatitis B virus (HBV)\u2013associated liver carcinogenesis. However, it remains unclear whether HBx\u2013expressing hepatic progenitor cells (HPCs) are attributed to liver tumor formation. In this study, by using HBx transgenic mice and a 3,5\u2013diethoxycarbonyl\u20131,4\u2013dihydrocollidine (DDC)\u2013induced liver injury model, the relationship between HBx expression and tumorigenicity of HPCs was analyzed. Compared with control mice, an elevated number of EpCAM+ cells with characteristics of HPCs was observed in HBx mice after 1 month and 4 months of DDC diet feeding. All HBx transgenic mice developed liver tumors characterized by histological features of both hepatocellular carcinoma (HCC) and cholangiocarcinoma after 7 months of DDC feeding. Notably, EpCAM+ HPCs isolated from premalignant HBx mice exposed to a DDC diet for 4 months formed subcutaneous mixed\u2013lineage tumors (four out of six) in nonobese diabetic\/severe\u2013combined immunodeficient (NOD\/SCID) mice, and none of the cells from wildtype (WT) induced tumor, indicating that HBx may induce malignant transformation of HPCs that contributes to tumorigenesis. We also found higher titers of circulating interleukin (IL)\u20136, activities of IL\u20136\/STAT3, and Wnt\/\u03b2\u2013catenin signaling pathways in HBx transgenic mice, suggesting HBx may induce intrinsic changes in HPCs by way of the above signaling that enables HPCs with tumorigenicity potential. Finally, clinical evidence showed that high HBx expression in human HBV\u2013related HCC was statistically associated with expansion of EpCAM+ or OV6+ tumor cells and aggressive clinicopathologic features.<\/jats:bold>\n                      <jats:bold>Conclusion<\/jats:bold>\n                      <jats:bold>: HBx induces intrinsic cellular transformation promoting the expansion and tumorigenicity of HPCs in DDC\u2013treated mice, which may be a possible origin for liver cancer induced by chronic hepatitis infection. (Hepatology 2012)<\/jats:bold>\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/hep.24675","type":"journal-article","created":{"date-parts":[[2011,9,19]],"date-time":"2011-09-19T13:54:03Z","timestamp":1316440443000},"page":"108-120","update-policy":"https:\/\/doi.org\/10.1097\/lww.0000000000001000","source":"Crossref","is-referenced-by-count":125,"title":["Hepatitis B Virus X (HBx) Induces Tumorigenicity of Hepatic Progenitor Cells in 3,5\u2013Diethoxycarbonyl\u20131,4\u2013Dihydrocollidine\u2013Treated HBx Transgenic Mice"],"prefix":"10.1097","volume":"55","author":[{"given":"Chao","family":"Wang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wen","family":"Yang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"He\u2013Xin","family":"Yan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tao","family":"Luo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jian","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liang","family":"Tang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fu\u2013Quan","family":"Wu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hui\u2013Lu","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Le\u2013Xing","family":"Yu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Long\u2013Yi","family":"Zheng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yu\u2013Qiong","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei","family":"Dong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ya\u2013Qin","family":"He","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qiong","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shan\u2013Shan","family":"Zou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yan","family":"Lin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liang","family":"Hu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhong","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Meng\u2013Chao","family":"Wu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hong\u2013Yang","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","reference":[{"key":"R2-14-20241201","doi-asserted-by":"crossref","first-page":"533","DOI":"10.1038\/286533a0","article-title":"Presence of integrated hepatitis B virus DNA sequences in cellular DNA of human hepatocellular carcinoma.","volume":"286","author":"Brechot","year":"1980","journal-title":"Nature"},{"key":"R3-14-20241201","doi-asserted-by":"crossref","first-page":"75","DOI":"10.1016\/S0065-230X(09)03004-8","article-title":"Hepatitis B virus X protein molecular functions and its role in virus life cycle and pathogenesis.","volume":"103","author":"Benhenda","year":"2009","journal-title":"Adv Cancer Res"},{"key":"R4-14-20241201","doi-asserted-by":"crossref","first-page":"21941","DOI":"10.1074\/jbc.M109.014563","article-title":"Deregulated direct targets of the hepatitis B virus (HBV) protein, HBx, identified through chromatin immunoprecipitation and expression microarray profiling.","volume":"284","author":"Sung","year":"2009","journal-title":"J Biol Chem"},{"key":"R5-14-20241201","doi-asserted-by":"crossref","first-page":"318","DOI":"10.1002\/hep.20076","article-title":"HBsAg and HBx knocked into the p21 locus causes hepatocellular carcinoma in mice.","volume":"39","author":"Wang","year":"2004","journal-title":"HEPATOLOGY"},{"key":"R6-14-20241201","first-page":"368","article-title":"Promotion of growth and differentiation of rat ductular oval cells in primary culture.","volume":"48","author":"Germain","year":"1988","journal-title":"Cancer Res"},{"key":"R7-14-20241201","doi-asserted-by":"crossref","first-page":"1353","DOI":"10.1002\/hep.20178","article-title":"2-Acetylaminofluorene dose-dependent differentiation of rat oval cells into hepatocytes: confocal and electron microscopic studies.","volume":"39","author":"Paku","year":"2004","journal-title":"HEPATOLOGY"},{"issue":"Suppl 1","key":"R8-14-20241201","doi-asserted-by":"crossref","first-page":"11881","DOI":"10.1073\/pnas.1734199100","article-title":"The origin and liver repopulating capacity of murine oval cells.","volume":"100","author":"Wang","year":"2003","journal-title":"Proc Natl Acad Sci U S A"},{"key":"R9-14-20241201","doi-asserted-by":"crossref","first-page":"433","DOI":"10.1002\/hep.510270218","article-title":"Hepatic oval cells express the hematopoietic stem cell marker Thy-1 in the rat.","volume":"27","author":"Petersen","year":"1998","journal-title":"HEPATOLOGY"},{"key":"R10-14-20241201","doi-asserted-by":"crossref","first-page":"1579","DOI":"10.1053\/j.gastro.2007.08.036","article-title":"Wntbeta-catenin signaling in murine hepatic transit amplifying progenitor cells.","volume":"133","author":"Hu","year":"2007","journal-title":"Gastroenterology"},{"key":"R11-14-20241201","doi-asserted-by":"crossref","first-page":"288","DOI":"10.1002\/hep.21973","article-title":"Wntbeta-catenin signaling mediates oval cell response in rodents.","volume":"47","author":"Apte","year":"2008","journal-title":"HEPATOLOGY"},{"key":"R12-14-20241201","doi-asserted-by":"crossref","first-page":"4287","DOI":"10.1158\/0008-5472.CAN-07-6691","article-title":"Wntbeta-catenin signaling contributes to activation of normal and tumorigenic liver progenitor cells.","volume":"68","author":"Yang","year":"2008","journal-title":"Cancer Res"},{"key":"R13-14-20241201","doi-asserted-by":"crossref","first-page":"2445","DOI":"10.1073\/pnas.0705395105","article-title":"Progenitorstem cells give rise to liver cancer due to aberrant TGF-beta and IL-6 signaling.","volume":"105","author":"Tang","year":"2008","journal-title":"Proc Natl Acad Sci U S A"},{"key":"R14-14-20241201","doi-asserted-by":"crossref","first-page":"937","DOI":"10.1053\/j.gastro.2007.06.016","article-title":"Enhanced self-renewal capability in hepatic stemprogenitor cells drives cancer initiation.","volume":"133","author":"Chiba","year":"2007","journal-title":"Gastroenterology"},{"key":"R15-14-20241201","doi-asserted-by":"crossref","first-page":"8248","DOI":"10.1073\/pnas.0912203107","article-title":"The Hippo-Salvador pathway restrains hepatic oval cell proliferation, liver size, and liver tumorigenesis.","volume":"107","author":"Lee","year":"2010","journal-title":"Proc Natl Acad Sci U S A"},{"key":"R16-14-20241201","doi-asserted-by":"crossref","first-page":"1964","DOI":"10.1002\/hep.22558","article-title":"Flow cytometric isolation and clonal identification of self-renewing bipotent hepatic progenitor cells in adult mouse liver.","volume":"48","author":"Suzuki","year":"2008","journal-title":"HEPATOLOGY"},{"key":"R17-14-20241201","doi-asserted-by":"crossref","first-page":"537","DOI":"10.1016\/S0002-9440(10)65299-6","article-title":"Oval cell numbers in human chronic liver diseases are directly related to disease severity.","volume":"154","author":"Lowes","year":"1999","journal-title":"Am J Pathol"},{"key":"R18-14-20241201","doi-asserted-by":"crossref","first-page":"1951","DOI":"10.1242\/dev.031369","article-title":"Potential hepatic stem cells reside in EpCAM cells of normal and injured mouse liver.","volume":"136","author":"Okabe","year":"2009","journal-title":"Development"},{"key":"R19-14-20241201","doi-asserted-by":"crossref","first-page":"e2493","DOI":"10.1371\/journal.pone.0002493","article-title":"Hepatotoxin-induced changes in the adult murine liver promote MYC-induced tumorigenesis.","volume":"3","author":"Beer","year":"2008","journal-title":"PLoS One"},{"key":"R20-14-20241201","doi-asserted-by":"crossref","first-page":"650","DOI":"10.1111\/j.1067-1927.2004.12605.x","article-title":"Direct effects of interleukin-6 on liver progenitor oval cells in culture.","volume":"12","author":"Matthews","year":"2004","journal-title":"Wound Repair Regen"},{"key":"R21-14-20241201","doi-asserted-by":"crossref","first-page":"26","DOI":"10.1016\/j.jhep.2010.08.006","article-title":"Hepatitis B virus X protein stimulates IL-6 expression in hepatocytes via a MyD88-dependent pathway.","volume":"54","author":"Xiang","year":"2011","journal-title":"J Hepatol"},{"key":"R22-14-20241201","doi-asserted-by":"crossref","first-page":"159","DOI":"10.1016\/j.molcel.2005.06.009","article-title":"Erk associates with and primes GSK-3beta for its inactivation resulting in upregulation of beta-catenin.","volume":"19","author":"Ding","year":"2005","journal-title":"Mol Cell"},{"key":"R23-14-20241201","doi-asserted-by":"crossref","first-page":"1012","DOI":"10.1053\/j.gastro.2008.12.004","article-title":"EpCAM-positive hepatocellular carcinoma cells are tumor-initiating cells with stemprogenitor cell features.","volume":"136","author":"Yamashita","year":"2009","journal-title":"Gastroenterology"},{"key":"R24-14-20241201","doi-asserted-by":"crossref","first-page":"1253","DOI":"10.1056\/NEJMra061808","article-title":"Cancer stem cells.","volume":"355","author":"Jordan","year":"2006","journal-title":"N Engl J Med"},{"key":"R25-14-20241201","doi-asserted-by":"crossref","first-page":"2800","DOI":"10.1200\/JCO.2007.15.5945","article-title":"Liver cancer stem cells.","volume":"26","author":"Sell","year":"2008","journal-title":"J Clin Oncol"},{"key":"R26-14-20241201","doi-asserted-by":"crossref","first-page":"2170","DOI":"10.1053\/j.gastro.2010.09.002","article-title":"Expansion of hepatic tumor progenitor cells in Pten-null mice requires liver injury and is reversed by loss of AKT2.","volume":"139","author":"Galicia","year":"2010","journal-title":"Gastroenterology"},{"key":"R28-14-20241201","doi-asserted-by":"crossref","first-page":"410","DOI":"10.1038\/nm1377","article-title":"A novel prognostic subtype of human hepatocellular carcinoma derived from hepatic progenitor cells.","volume":"12","author":"Lee","year":"2006","journal-title":"Nat Med"},{"key":"R29-14-20241201","doi-asserted-by":"crossref","first-page":"675","DOI":"10.1016\/0092-8674(95)90039-X","article-title":"Mice lacking p21CIP1WAF1 undergo normal development, but are defective in G1 checkpoint control.","volume":"82","author":"Deng","year":"1995","journal-title":"Cell"},{"key":"R30-14-20241201","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-dependent IL-6 production.","volume":"317","author":"Naugler","year":"2007","journal-title":"Science"},{"key":"R31-14-20241201","doi-asserted-by":"crossref","first-page":"39","DOI":"10.1111\/j.1478-3231.2005.01191.x","article-title":"Serum cytokine and soluble cytokine receptor levels in patients with non-alcoholic steatohepatitis.","volume":"26","author":"Abiru","year":"2006","journal-title":"Liver Int"},{"key":"R32-14-20241201","doi-asserted-by":"crossref","first-page":"2766","DOI":"10.1002\/ijc.24281","article-title":"High serum interleukin-6 level predicts future hepatocellular carcinoma development in patients with chronic hepatitis B.","volume":"124","author":"Wong","year":"2009","journal-title":"Int J Cancer"},{"key":"R33-14-20241201","doi-asserted-by":"crossref","first-page":"1298","DOI":"10.1002\/hep.21651","article-title":"WNTbeta-catenin signaling in liver health and disease.","volume":"45","author":"Thompson","year":"2007","journal-title":"HEPATOLOGY"},{"key":"R34-14-20241201","doi-asserted-by":"crossref","first-page":"1683","DOI":"10.1002\/hep.20245","article-title":"Hepatitis B virus X protein is essential for the activation of Wntbeta-catenin signaling in hepatoma cells.","volume":"39","author":"Cha","year":"2004","journal-title":"HEPATOLOGY"},{"key":"R35-14-20241201","doi-asserted-by":"crossref","first-page":"1444","DOI":"10.1002\/ijc.22476","article-title":"CD133 positive hepatocellular carcinoma cells possess high capacity for tumorigenicity.","volume":"120","author":"Yin","year":"2007","journal-title":"Int J Cancer"},{"key":"R36-14-20241201","doi-asserted-by":"crossref","first-page":"2542","DOI":"10.1053\/j.gastro.2007.04.025","article-title":"Identification and characterization of tumorigenic liver cancer stemprogenitor cells.","volume":"132","author":"Ma","year":"2007","journal-title":"Gastroenterology"},{"key":"R37-14-20241201","doi-asserted-by":"crossref","first-page":"3701","DOI":"10.1158\/0008-5472.CAN-10-3951","article-title":"Does the hepatitis B antigen HBx promote the appearance of liver cancer stem cells?","volume":"71","author":"Arzumanyan","year":"2011","journal-title":"Cancer Res"}],"container-title":["Hepatology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1002%2Fhep.24675","content-type":"unspecified","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/journals.lww.com\/01515467-201201000-00014","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,12,1]],"date-time":"2024-12-01T08:39:16Z","timestamp":1733042356000},"score":1,"resource":{"primary":{"URL":"https:\/\/journals.lww.com\/01515467-201201000-00014"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2012,1]]},"references-count":35,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2012]]}},"URL":"https:\/\/doi.org\/10.1002\/hep.24675","relation":{},"ISSN":["0270-9139"],"issn-type":[{"value":"0270-9139","type":"print"}],"subject":[],"published":{"date-parts":[[2012,1]]}}}