| First Author | Liu Y | Year | 2015 |
| Journal | Stem Cells | Volume | 33 |
| Issue | 12 | Pages | 3569-80 |
| PubMed ID | 26033745 | Mgi Jnum | J:228580 |
| Mgi Id | MGI:5707986 | Doi | 10.1002/stem.2072 |
| Citation | Liu Y, et al. (2015) Osteopontin Promotes Hepatic Progenitor Cell Expansion and Tumorigenicity via Activation of beta-Catenin in Mice. Stem Cells 33(12):3569-80 |
| abstractText | 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 beta-catenin activity, expressions of OPN and beta-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 beta-catenin via binding to alphav 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 beta-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. |
