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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\u201312 months to induce tumorigenesis. Epithelial cell adhesion molecule EpCAM+CD45\u2212 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 \u03b2-catenin activity, expressions of OPN and \u03b2-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 \u03b2-catenin via binding to \u03b1v 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 \u03b2-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 \u00a02015;33:3569\u20133580<\/jats:p>","DOI":"10.1002\/stem.2072","type":"journal-article","created":{"date-parts":[[2015,5,28]],"date-time":"2015-05-28T17:09:18Z","timestamp":1432832958000},"page":"3569-3580","source":"Crossref","is-referenced-by-count":27,"title":["Osteopontin Promotes Hepatic Progenitor Cell Expansion and Tumorigenicity via Activation of \u03b2-Catenin in Mice"],"prefix":"10.1093","volume":"33","author":[{"given":"Yingying","family":"Liu","sequence":"first","affiliation":[{"name":"International Joint Cancer Institute The Second Military Medical University, Shanghai, People's Republic of China"},{"name":"Changhai Hospital The Second Military Medical University, Shanghai, People's Republic of China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lei","family":"Cao","sequence":"additional","affiliation":[{"name":"International Joint Cancer Institute The Second Military Medical University, Shanghai, People's Republic of 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