GSK-3β suppresses the proliferation of rat hepatic oval cells through modulating Wnt/β-catenin signaling pathway

Abstract

Aim: Glycogen synthase kinase 3β (GSK-3β) plays a crucial role in hepatic biology, including liver development, regeneration, proliferation and carcinogenesis. In this study we investigated the role of GSK-3β in regulation of growth of hepatic oval cells in vitro and in liver regeneration in partially hepatectomized rats. Methods: WB-F344 cells, the rat hepatic stem-like epithelial cells, were used as representative of oval cells. Cell viability was examined using a WST-8 assay. The cells were transfected with a recombinant lentivirus expressing siRNA against GSK-3β (GSK3βRNAiLV) or a lentivirus that overexpressed GSK-3β (GC-GSK-3βLV). Adult rats underwent partial (70%) hepatectomy, and liver weight and femur length were measured at d 7 after the surgery. The expression of GSK-3β, phospho-Ser 9 -GSK-3β, β-catenin and cyclin D1 was examined with immunoblotting assays or immunohistochemistry. Results: Treatment of WB-F344 cells with the GSK-3β inhibitor SB216763 (5 and 10 µmol/L) dose-dependently increased the levels of phospho-Ser 9 -GSK-3β, but not the levels of total GSK-3β, and promoted the cell proliferation. Knockout of GSK-3β with GSK-3βRNAiLV increased the cell proliferation, whereas overexpression of GSK-3β with GC-GSK-3βLV decreased the proliferation. Both SB216763 and GSK-3βRNAiLV significantly increased the levels of β-catenin and cyclin D1 in the cells, whereas GSK-3β overexpression decreased their levels. In rats with a partial hepatectomy, administration of SB216763 (2 mg/kg, ip) significantly increased the number of oval cells, the levels of phospho-Ser 9 -GSK-3β, β-catenin and cyclin D1 in liver, as well as the ratio of liver weight to femur length at d 7 after the surgery. Conclusion: GSK-3β suppresses the proliferation of hepatic oval cells by modulating the Wnt/β-catenin signaling pathway.

MicroRNA-27a Promotes the Proliferation and Invasiveness of Colon Cancer Cells by Targeting SFRP1 through the Wnt/β-Catenin Signaling Pathway

“…Glycogen synthase kinase-3β (GSK-3β), a widespread cellular serine/threonine kinase, plays a key role in the regulation of various signaling pathways, including Wnt/β-catenin signaling [35, 36]. In the Wnt pathway, GSK-3β is found in multimeric composites composed of the adenomatous polyposis coli (APC) protein, axin and β catenin [37], where it causes phosphorylation of the N-terminal Ser/Thr in β-catenin [38]. It was revealed that the suppression of GSK-3β can activate Wnt signaling and β-catenin through dephosphorylation, where GSK-3β functions as an inhibitor of the Wnt pathway [38].…”

“…In the Wnt pathway, GSK-3β is found in multimeric composites composed of the adenomatous polyposis coli (APC) protein, axin and β catenin [37], where it causes phosphorylation of the N-terminal Ser/Thr in β-catenin [38]. It was revealed that the suppression of GSK-3β can activate Wnt signaling and β-catenin through dephosphorylation, where GSK-3β functions as an inhibitor of the Wnt pathway [38]. Wnts are secreted proteins that bind to a Frizzled receptor and lipoprotein receptor-related protein 5 (LRP5) or LRP6 co-receptor, which results in an increased level of β-catenin because its degradation via the proteasome is prevented [39].…”

Lineage tracing reveals conversion of liver sinusoidal endothelial cells into hepatocytes

“…Our finding was in accordance with the previous report that 1.4% of all hepatocytes were derived from nonhepatocytes during liver regeneration after two-thirds PH (Malato et al 2011). Unlike LSECs, progenitor cells such as oval cells and/or hepatic stellate cells have been previously reported to convert into hepatocytes during liver regeneration Ji et al 2015). Since Tie2-Cre-mediated excision could also occur in non-endothelial populations such as mesenchymal cells surrounding the vitelline artery (Li et al 2006;Lan et al 2014), mice expressing Cre recombinase under the control of the VE-Cadherin promoter (Zovein et al 2008) were used to trace the fate of endothelial cells during liver regeneration.…”

“…; Ji et al . ). Since Tie2‐Cre‐mediated excision could also occur in non‐endothelial populations such as mesenchymal cells surrounding the vitelline artery (Li et al .…”

GSK-3β inhibitor TWS119 attenuates rtPA-induced hemorrhagic transformation and activates the Wnt/β-catenin signaling pathway after acute ischemic stroke in rats

“…Because β-catenin is a key component of the Wnt/β-catenin pathway, enhancing its expression activates the downstream signaling pathway [38]. In our study, we found that TWS119 increased the expression of claudin-3 compared with that in the rtPA group.…”