title: Gankyrin drives malignant transformation of chronic liver damage-mediated fibrosis via the Rac1/JNK pathway.
abstract: Hepatocarcinogenesis is a complex process involving chronic liver injury, inflammation, unregulated wound healing, subsequent fibrosis and carcinogenesis. To decipher the molecular mechanism underlying transition from chronic liver injury to dysplasia, we investigated the oncogenic role of gankyrin (PSMD10 or p28GANK) 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 CCl4 treatment, hepatocyte-specific gankyrin-overexpressing mice (gankyrinhep) exhibited malignant transformation from liver fibrosis to tumors even under single CCl4 administration, whereas wild-type mice merely experienced fibrosis. Consistently, enhanced hepatic injury, severe inflammation and strengthened compensatory proliferation occurred in gankyrinhep) mice during CCl4 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 CCl4-induced carcinogenesis in gankyrinhep 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.
authors.affiliation: 1] Model Animal Research Center and MOE Key Laboratory of Model Animal for Disease Study, Nanjing University, Nanjing 210061, China [2] International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute/Hospital, Shanghai 200438, China.
authors.forename: X
authors.initials: X
authors.lastname: Zhao
authors.affiliation: 1] International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute/Hospital, Shanghai 200438, China [2] National Center for Liver Cancer, Shanghai 200438, China.
authors.forename: J
authors.initials: J
authors.lastname: Fu
authors.affiliation: International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute/Hospital, Shanghai 200438, China.
authors.forename: A
authors.initials: A
authors.lastname: Xu
authors.affiliation: 1] International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute/Hospital, Shanghai 200438, China [2] National Center for Liver Cancer, Shanghai 200438, China.
authors.forename: L
authors.initials: L
authors.lastname: Yu
authors.affiliation: International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute/Hospital, Shanghai 200438, China.
authors.forename: J
authors.initials: J
authors.lastname: Zhu
authors.affiliation: International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute/Hospital, Shanghai 200438, China.
authors.forename: R
authors.initials: R
authors.lastname: Dai
authors.affiliation: International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute/Hospital, Shanghai 200438, China.
authors.forename: B
authors.initials: B
authors.lastname: Su
authors.affiliation: International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute/Hospital, Shanghai 200438, China.
authors.forename: T
authors.initials: T
authors.lastname: Luo
authors.affiliation: International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute/Hospital, Shanghai 200438, China.
authors.forename: N
authors.initials: N
authors.lastname: Li
authors.affiliation: International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute/Hospital, Shanghai 200438, China.
authors.forename: W
authors.initials: W
authors.lastname: Qin
authors.affiliation: International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute/Hospital, Shanghai 200438, China.
authors.forename: B
authors.initials: B
authors.lastname: Wang
authors.affiliation: International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute/Hospital, Shanghai 200438, China.
authors.forename: J
authors.initials: J
authors.lastname: Jiang
authors.affiliation: MOE Key Laboratory of Bioinformatics and Bioinformatics Division, TNLIST, Department of Antomation, Tsinghua University, Beijing 100084, China.
authors.forename: S
authors.initials: S
authors.lastname: Li
authors.affiliation: 1] International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute/Hospital, Shanghai 200438, China [2] National Center for Liver Cancer, Shanghai 200438, China.
authors.forename: Y
authors.initials: Y
authors.lastname: Chen
authors.affiliation: 1] Model Animal Research Center and MOE Key Laboratory of Model Animal for Disease Study, Nanjing University, Nanjing 210061, China [2] International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute/Hospital, Shanghai 200438, China [3] National Center for Liver Cancer, Shanghai 200438, China [4] State Key Laboratory of Oncogenes and Related Genes, Cancer Institute of Renji Hospital, Shanghai Jiaotong University, Shanghai 200032, China.
authors.forename: H
authors.initials: H
authors.lastname: Wang
mesh_terms: D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D002908:Chronic Disease; D006801:Humans; D008103:Liver Cirrhosis / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D008113:Liver Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D048670:MAP Kinase Kinase 4 / Q000378:metabolism*; D020935:MAP Kinase Signaling System; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D046988:Proteasome Endopeptidase Complex / Q000235:genetics / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D020830:rac1 GTP-Binding Protein / Q000378:metabolism*
chemical_list: C403591:PSMD10 protein, human; D011518:Proto-Oncogene Proteins; C107953:RAC1 protein, human; D048670:MAP Kinase Kinase 4; D046988:Proteasome Endopeptidase Complex; D020830:rac1 GTP-Binding Protein