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To decipher the molecular mechanism underlying transition from chronic liver injury to dysplasia, we investigated the oncogenic role of gankyrin (PSMD10 or p28<jats:sup>GANK<\/jats:sup>) during malignant transformation in a transgenic mouse model. Here, we find that gankyrin increased in patients with cirrhosis. In addition to more severe liver fibrosis and tumorigenesis after DEN plus CCl<jats:sub>4<\/jats:sub> treatment, hepatocyte-specific gankyrin-overexpressing mice (gankyrin<jats:sup>hep<\/jats:sup>) exhibited malignant transformation from liver fibrosis to tumors even under single CCl<jats:sub>4<\/jats:sub> administration, whereas wild-type mice merely experienced fibrosis. Consistently, enhanced hepatic injury, severe inflammation and strengthened compensatory proliferation occurred in gankyrin<jats:sup>hep<\/jats:sup> mice during CCl<jats:sub>4<\/jats:sub> performance. This correlated with augmented expressions of cell cycle-related genes and abnormal activation of Rac1\/c-jun N-terminal kinase (JNK). Pharmacological inhibition of the Rac1\/JNK pathway attenuated hepatic fibrosis and prevented CCl<jats:sub>4<\/jats:sub>-induced carcinogenesis in gankyrin<jats:sup>hep<\/jats:sup> mice. Together, these findings suggest that gankyrin promotes liver fibrosis\/cirrhosis progression into hepatocarcinoma relying on a persistent liver injury and inflammatory microenvironment. Blockade of Rac1\/JNK activation impeded gankyrin-mediated hepatocytic malignant transformation, indicating the combined inhibition of gankyrin and Rac1\/JNK as a potential prevention mechanism for cirrhosis transition.<\/jats:p>","DOI":"10.1038\/cddis.2015.120","type":"journal-article","created":{"date-parts":[[2015,5,7]],"date-time":"2015-05-07T13:02:17Z","timestamp":1431003737000},"page":"e1751-e1751","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":45,"title":["Gankyrin drives malignant transformation of chronic liver damage-mediated fibrosis via the Rac1\/JNK pathway"],"prefix":"10.1038","volume":"6","author":[{"given":"X","family":"Zhao","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"J","family":"Fu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"A","family":"Xu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"L","family":"Yu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"J","family":"Zhu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"R","family":"Dai","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"B","family":"Su","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"T","family":"Luo","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"N","family":"Li","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"W","family":"Qin","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"B","family":"Wang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"J","family":"Jiang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"S","family":"Li","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Y","family":"Chen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"H","family":"Wang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2015,5,7]]},"reference":[{"key":"BFcddis2015120_CR1","doi-asserted-by":"publisher","first-page":"860","DOI":"10.1038\/nature01322","volume":"420","author":"LM Coussens","year":"2002","unstructured":"Coussens LM, Werb Z . 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