Overexpression of Leucine-Rich Repeat-Containing G Protein-Coupled Receptor 5 (LGR5) Represents a Typical Wnt/β-Catenin Pathway-Activated Hepatocellular Carcinoma.

BACKGROUND: Hepatocellular carcinoma (HCC) is one of the most common and most frequently lethal cancers worldwide. Although many advances have been made in the analysis of multistage hepatocarcinogenesis, we still lack information to guide adequate clinical management options for HCC. A large number of genetic alterations occur during hepatocarcinogenesis, and many genetic studies have indicated that one of the most frequently mutated oncogenes found in HCC is β-catenin.
SUMMARY: 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. KEY MESSAGES: Recent efforts on the molecular classification of HCC have led us to new strategies for dealing with HCC. These specific signatures may predict the risk of recurrence or the patient survival rate, which affect the outlook and may suggest treatment strategies for HCC patients.