title: Downregulation of AZGP1 by Ikaros and histone deacetylase promotes tumor progression through the PTEN/Akt and CD44s pathways in hepatocellular carcinoma.
abstract: Increasing evidence has shown that zinc-alpha2-glycoprotein (AZGP1) is associated with the progression and prognosis of several tumor types. However, little is known regarding the underlying molecular mechanisms of AZGP1 in hepatocellular carcinoma (HCC). In this study, we report that transcription factor Ikaros bound to the AZGP1 promoter and increased its expression in HCC cells. The downregulation of AZGP1 was associated with histone deacetylation in HCC. In addition, the positive feedback regulation via acetylation of histone H4-mediated transactivation of the Ikaros promoter and the Ikaros-mediated transactivation of the acetylation of histone H4 were crucial for regulating AZGP1 expression in HCC cells. Moreover, low serum AZGP1 level in HCC patients was associated with poor prognosis. The ectopic overexpression of AZGP1 or recombinant AZGP1 protein inhibited HCC cell proliferation, migration and invasion in vitro and in vivo, whereas silencing AZGP1 expression resulted in increased cell proliferation, migration and invasion in vitro. In addition, we found that AZGP1 inhibited cell migration and invasion through the regulation of the PTEN/Akt and CD44s pathways. Collectively, our findings revealed the molecular mechanism of AZGP1 expression in HCC, providing new insights into the mechanisms underlying tumor progression.
authors.affiliation: State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiaotong University School of Medicine, 25/Ln 2200, Xietu Road, Shanghai 200032, China.
authors.forename: Hua
authors.initials: H
authors.lastname: Tian
authors.affiliation: State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiaotong University School of Medicine, 25/Ln 2200, Xietu Road, Shanghai 200032, China.
authors.forename: Chao
authors.initials: C
authors.lastname: Ge
authors.affiliation: State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiaotong University School of Medicine, 25/Ln 2200, Xietu Road, Shanghai 200032, China.
authors.forename: Fangyu
authors.initials: F
authors.lastname: Zhao
authors.affiliation: State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiaotong University School of Medicine, 25/Ln 2200, Xietu Road, Shanghai 200032, China.
authors.forename: Miaoxin
authors.initials: M
authors.lastname: Zhu
authors.affiliation: State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiaotong University School of Medicine, 25/Ln 2200, Xietu Road, Shanghai 200032, China.
authors.forename: Lin
authors.initials: L
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiaotong University School of Medicine, 25/Ln 2200, Xietu Road, Shanghai 200032, China.
authors.forename: Qi
authors.initials: Q
authors.lastname: Huo
authors.affiliation: State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiaotong University School of Medicine, 25/Ln 2200, Xietu Road, Shanghai 200032, China.
authors.forename: Hong
authors.initials: H
authors.lastname: Li
authors.affiliation: Qi Dong Liver Cancer Institute, Qi Dong 226200, Jiangsu Province, China.
authors.forename: Taoyang
authors.initials: T
authors.lastname: Chen
authors.affiliation: Department of General Surgery, the First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310000, China and.
authors.forename: Haiyang
authors.initials: H
authors.lastname: Xie
authors.affiliation: Cancer Institute of Guangxi, Nanning 530000, China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Cui
authors.affiliation: State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiaotong University School of Medicine, 25/Ln 2200, Xietu Road, Shanghai 200032, China.
authors.forename: Ming
authors.initials: M
authors.lastname: Yao
authors.affiliation: State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiaotong University School of Medicine, 25/Ln 2200, Xietu Road, Shanghai 200032, China.
authors.forename: Jinjun
authors.initials: J
authors.lastname: Li
mesh_terms: D054392:Adipokines; D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000235:genetics* / Q000473:pathology; D002352:Carrier Proteins / Q000096:biosynthesis* / Q000235:genetics; D002465:Cell Movement / Q000235:genetics; D049109:Cell Proliferation / Q000235:genetics; D058750:Epithelial-Mesenchymal Transition / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic; D006023:Glycoproteins / Q000096:biosynthesis* / Q000235:genetics; D006655:Histone Deacetylases / Q000235:genetics; D006801:Humans; D018960:Hyaluronan Receptors / Q000235:genetics; D051740:Ikaros Transcription Factor / Q000235:genetics; D008113:Liver Neoplasms / Q000235:genetics* / Q000473:pathology; D051379:Mice; D051058:Oncogene Protein v-akt / Q000235:genetics; D051059:PTEN Phosphohydrolase / Q000235:genetics; D015398:Signal Transduction; D023041:Xenograft Model Antitumor Assays; D000090203:Zn-Alpha-2-Glycoprotein
chemical_list: D054392:Adipokines; D002352:Carrier Proteins; D006023:Glycoproteins; D006655:Histone Deacetylases; D018960:Hyaluronan Receptors; D051740:Ikaros Transcription Factor; D051058:Oncogene Protein v-akt; D051059:PTEN Phosphohydrolase; C488891:AZGP1 protein, human; D000090203:Zn-Alpha-2-Glycoprotein; C473647:CD44S antigen; C497239:IKZF1 protein, human; C494929:PTEN protein, human