title: Osteopontin Promotes Hepatic Progenitor Cell Expansion and Tumorigenicity via Activation of β-Catenin in Mice.
abstract: Upregulation of osteopontin (OPN) has been found in hepatic progenitor cells (HPCs) in several liver diseases with portal biliary proliferation. Here, we investigated the role of HPC-derived autocrine OPN in regulating HPC expansion, migration, and hepatocarcinogenesis in mice. Five-week-old, weighing between 18 and 20 g of either wild type (WT) or OPN gene knockout (OPN-KO) male mice were treated with modified choline-deficient, ethionine-supplemented diet (modified choline-deficient [MCDE]) for 2 weeks to induce HPC production, or 6-12 months to induce tumorigenesis. Epithelial cell adhesion molecule EpCAM(+) CD45(-) cells isolated from mouse liver and liver epithelial progenitor cells were used for in vitro study. OPN was blocked by specific antibody or RNAi-mediated silence to investigate the role of OPN. To evaluate correlation between OPN expression and β-catenin activity, expressions of OPN and β-catenin were assessed in human liver cancer specimens. We found autocrine OPN promotes HPC expansion and migration by decreasing membranous E-cadherin and increasing free cytoplasmic β-catenin via binding to αv integrin and activating Src activity. Depletion of OPN significantly attenuated MCDE-induced hepatocarcinogenesis. Clinical evidence revealed a strong correlation of high OPN expression with cytoplasmic/nuclear expression of β-catenin in 43 cases of human combined hepatocellular carcinoma and cholangiocarcinoma and mixed intrahepatic cholangiocarcinoma and 80 cases of hepatocellular carcinoma. Our results indicate that autocrine OPN plays a crucial role in HPC expansion, migration, and subsequent oncogenic transformation of HPCs, which may provide a new insight into hepatocarcinogenesis.
authors.affiliation: International Joint Cancer Institute, The Second Military Medical University, Shanghai, People's Republic of China.|Changhai Hospital, The Second Military Medical University, Shanghai, People's Republic of China.
authors.forename: Yingying
authors.initials: Y
authors.lastname: Liu
authors.affiliation: International Joint Cancer Institute, The Second Military Medical University, Shanghai, People's Republic of China.|Clinical Immunology Laboratory, The First Affiliated Hospital of Suzhou University, Suzhou, Jiangsu, People's Republic of China.
authors.forename: Lei
authors.initials: L
authors.lastname: Cao
authors.affiliation: International Joint Cancer Institute, The Second Military Medical University, Shanghai, People's Republic of China.
authors.forename: Rui
authors.initials: R
authors.lastname: Chen
authors.affiliation: Changhai Hospital, The Second Military Medical University, Shanghai, People's Republic of China.
authors.forename: Xuyu
authors.initials: X
authors.lastname: Zhou
authors.affiliation: International Joint Cancer Institute, The Second Military Medical University, Shanghai, People's Republic of China.
authors.forename: Xiaoyu
authors.initials: X
authors.lastname: Fan
authors.affiliation: International Joint Cancer Institute, The Second Military Medical University, Shanghai, People's Republic of China.
authors.forename: Yingchao
authors.initials: Y
authors.lastname: Liang
authors.affiliation: International Joint Cancer Institute, The Second Military Medical University, Shanghai, People's Republic of China.
authors.forename: Rongjie
authors.initials: R
authors.lastname: Jia
authors.affiliation: International Joint Cancer Institute, The Second Military Medical University, Shanghai, People's Republic of China.
authors.forename: Hao
authors.initials: H
authors.lastname: Wang
authors.affiliation: International Joint Cancer Institute, The Second Military Medical University, Shanghai, People's Republic of China.
authors.forename: Guoke
authors.initials: G
authors.lastname: Liu
authors.affiliation: International Joint Cancer Institute, The Second Military Medical University, Shanghai, People's Republic of China.|PLA General Hospital Cancer Center, PLA postgraduate School of Medicine, Beijing, People's Republic of China.|Beijing Key Laboratory of Cell Engineering and Antibody, Beijing, People's Republic of China.
authors.forename: Yajun
authors.initials: Y
authors.lastname: Guo
authors.affiliation: International Joint Cancer Institute, The Second Military Medical University, Shanghai, People's Republic of China.|PLA General Hospital Cancer Center, PLA postgraduate School of Medicine, Beijing, People's Republic of China.|Beijing Key Laboratory of Cell Engineering and Antibody, Beijing, People's Republic of China.
authors.forename: Jian
authors.initials: J
authors.lastname: Zhao
mesh_terms: D000818:Animals; D019898:Autocrine Communication; D002460:Cell Line; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D008099:Liver / Q000378:metabolism* / Q000473:pathology; D008113:Liver Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D053495:Osteopontin / Q000235:genetics / Q000378:metabolism*; D013234:Stem Cells / Q000378:metabolism* / Q000473:pathology; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism*
chemical_list: C506896:Spp1 protein, mouse; D051176:beta Catenin; D053495:Osteopontin
keywords: Epithelial-mesenchymal transition; Hepatic progenitor cell; Hepatocarcinogenesis; Osteopontin