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. Fiveweek-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 1 CD45 2 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 b-catenin activity, expressions of OPN and b-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 b-catenin via binding to a v 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 b-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 SIGNIFICANCE STATEMENTIn this article, a modified choline-deficient, ethionine-supplemented diet (MCDE) murine model was employed to induce HPC expansion. OPN deficiency caused decreased HPC expansion, attenuated HPC migration, and less tumorigenesis, which clarified the roles of OPN in HPCs and their oncogenic transformation. These results provide a new sight of aurocrine OPN during chemical-induced HPC expansion and subsequent tumorigenesis and may have a potential for development of novel strategy for treatment of liver cancer.

Osteopontin facilitates tumor metastasis by regulating epithelial–mesenchymal plasticity

“…In accord with previous studies, 8, 16 sOPN induced EMT in cancer; whereas the nuclear OPN triggered MET through the AKT1/miR-429/ZEB axis through interaction with HIF2 α . In vivo studies and patient samples further supported the diverse roles of sOPN and iOPN in tumor metastasis.…”

Obesity-Induced Methylation of Osteopontin Contributes to Adipogenic Differentiation of Adipose-Derived Mesenchymal Stem Cells

“…Previous studies have shown that OPN works by binding to cell surface receptors [28], and integrin αν / β 1 and CD44 are indeed highly expressed on MSCs [29]. We then used specific antibodies against the OPN receptors to determine which receptors mediate the effect of OPN on ASC differentiation.…”

Stem/Progenitor Cell Niches Involved in Hepatic and Biliary Regeneration

“…HpSCs can activate stellate/endothelial cells via the Hedgehog (Hh) pathway resulting in release of types of matrix components (e.g., type IV collagen, laminin, syndecans, and glypicans) associated with normal liver regeneration [ 70 , 73 , 86 ]; other key paracrine signals include OPN and transforming growth factor- β 1 (TGF- β 1) which induce collagen-I deposition and other matrix components associated with fibrosis by stellate cells and MFs [ 87 , 88 ]. The OPN synthesized by HpSCs could also have an autocrine role in HpSC expansion and migration (via disruption of cell adhesion) [ 89 ]. In chronic pathological conditions, this cellular cross-talk of paracrine signals could be responsible in establishing a profibrogenic loop [ 57 ]; in fibrogenesis, MF activation is secondary to the expansion of the HpSC compartment mediated in part by the Hh pathway [ 90 ] along with signaling pathways induced by chronic injury [ 77 ].…”