Glypican 3 (GPC3) belongs to a family of glycosylphosphatidylinositol-anchored, cell-surface heparan sulfate proteoglycans. GPC3 is over-expressed in hepatocellular carcinomas (HCC). Loss-of-function mutations of GPC3 result in the Simpson-Golabi-Behmel syndrome, an X-linked disorder characterized by overgrowth of multiple organs, including liver. Our previous study showed that GPC3 plays a negative regulatory role in hepatocyte proliferation, and this effect may involve CD81, a cell membrane tetraspanin. To further investigate GPC3 in vivo, we engineered transgenic (TG) mice over-expressing GPC3 in liver under the control of the albumin promoter. GPC3 TG mice with hepatocyte-targeted over-expressed GPC3 develop normally compared with their non-transgenic littermates, but have a suppressed rate of hepatocyte proliferation and liver regeneration after partial hepatectomy (PHx). Moreover, gene array analysis revealed a series of changes in the gene expression profiles in TG mice, both in normal mice and during liver regeneration. In unoperated GPC3 TG mice there was over-expression of Runx3 (7.6 fold), C/EBPα (2.5 fold) and GABA A Receptor (2.9 fold) and Wnt7b (2.8 fold). There was down-regulation of IGF BP1 (8.4 fold), Rab2 (5.6 fold), beta Catenin (1.7 fold), TGF beta 1 (3.1 fold), Nodal (1.8 fold) and Yap (1.4 fold). Changes after hepatectomy included decreased expression in several cell cycle related genes.
Our results indicate that in GPC3 transgenic mice, hepatocyte over-expression of GPC3 suppresses hepatocyte proliferation and liver regeneration, and alters gene expression profiles in GPC3 TG mice, in which potential cell cycle related proteins and multiple other pathways are involved and affected.