Does overexpression of Leucine-Rich Repeat-Containing G Protein-Coupled Receptor 5 ( LGR5 ) represent a Typical Wnt/β-Catenin Pathway-Activated Hepatocellular Carcinoma?
Molecular subclassification of HCC based on gene expression signatures has identified a typical hepatocyte-like subclass of HCC harboring β-catenin mutations; this subclass is characterized by better histological differentiation and a less aggressive nature. We previously identified overexpression of the leucine-rich repeat-containing G protein-coupled receptor 5 (LGR5), also known as GPR49, in HCC with β-catenin mutations. LGR5 has been indicated as one of the downstream target genes of the Wnt signaling pathway; however, the functional role of LGR5 in cancer is largely unknown. We demonstrated that HCC cells transfected with LGR5 exhibited higher colony forming activity and were more resistant to a cytotoxic drug than the control HCC cells were. Overexpression of LGR5 also retarded cell migration. LGR5-transfected HCC cells formed nodule-type tumors in the livers of immunodeficient mice, whereas control cells formed more invasive tumors. Results of our recent research suggest that aberrant expression of LGR5 could regulate the epithelial cell phenotype and promotes HCC cell survival. HCC cells overexpressing LGR5 seem to represent a typical phenotype of a less aggressive HCC.
These observations indicate that mast cell degranulation stimulated by thrombin is necessary for the rapid induction of plasma HGF in intravascular thrombus-associated disorders.