Osteopontin Promotes Hepatic Progenitor Cell Expansion and Tumorigenicity via Activation of β-Catenin in Mice

• DOI: 10.1002/stem.2072
• Publication Date: 2015-05-28T17:09:18Z
• Authors: Yingying Liu; Lei Cao; Rui Chen; Xuyu Zhou; Xiaoyu Fan; Yingchao Liang; Rongjie Jia; Hao Wang; Guoke Liu; Yajun Guo; Jian Zhao
• Keywords: Male; Mice, Knockout; 0303 health sciences; Stem Cells; Liver Neoplasms; Cell Line; 3. Good health; Autocrine Communication; Mice; 03 medical and health sciences; Cell Transformation, Neoplastic; Liver; Animals; Humans; Osteopontin; beta Catenin

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. Stem Cells 2015;33:3569–3580