title: Overexpression of orphan G-protein-coupled receptor, Gpr49, in human hepatocellular carcinomas with beta-catenin mutations.
abstract: To identify the genes responsible for carcinogenesis and progression of hepatocellular carcinoma (HCC), we screened differentially expressed genes in several human HCC cell lines. Among these genes, Gpr49 was up-regulated in PLC/PRF/5 and HepG2. Gpr49 is a member of the glycoprotein hormone receptor subfamily, which includes the thyroid-stimulating hormone receptor (TSHR). However, Gpr49 remains to be an orphan G-protein-coupled receptor. By real-time quantitative reverse transcriptase polymerase chain reaction (RT-PCR) analysis, overexpression (>3-fold increase compared with the corresponding noncancerous liver tissue) of Gpr49 mRNA was observed in 18 of 38 (47%) HCCs compared with corresponding noncancerous livers. Clinicopathologically, overexpression of Gpr49 was frequently observed in HCC with mutation in beta-catenin exon 3 (14 of 16 cases, 87.5%). Moreover, introduction of mutant beta-catenin into mouse hepatocytes in culture caused up-regulation of the Gpr49 mouse homologue. Therefore, Gpr49 is likely to be a target gene activated by Wnt-signaling in HCC. In conclusion, although much is still unknown, Gpr49 may be critically involved in the development of HCCs with beta-catenin mutations and has the potential to be a new therapeutic target in the treatment of HCC.
authors.affiliation: Pathology Division, National Cancer Center Research Institute, Tokyo, Japan. Third Department of Internal Medicine, Hokkaido University Faculty of Medicine, Sapporo, Japan.
authors.forename: Yoshiya
authors.initials: Y
authors.lastname: Yamamoto
authors.forename: Michiie
authors.initials: M
authors.lastname: Sakamoto
authors.forename: Gen
authors.initials: G
authors.lastname: Fujii
authors.forename: Hitomi
authors.initials: H
authors.lastname: Tsuiji
authors.forename: Kengo
authors.initials: K
authors.lastname: Kenetaka
authors.forename: Masahiro
authors.initials: M
authors.lastname: Asaka
authors.forename: Setsuo
authors.initials: S
authors.lastname: Hirohashi
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000235:genetics*; D002460:Cell Line; D003001:Cloning, Molecular; D003598:Cytoskeletal Proteins / Q000235:genetics*; D005260:Female; D015870:Gene Expression; D049452:Green Fluorescent Proteins; D022781:Hepatocytes / Q000378:metabolism; D006801:Humans; D008113:Liver Neoplasms / Q000235:genetics*; D008164:Luminescent Proteins / Q000235:genetics; D008297:Male; D051379:Mice; D008875:Middle Aged; D016297:Mutagenesis, Site-Directed; D009154:Mutation; D012333:RNA, Messenger / Q000032:analysis; D011956:Receptors, Cell Surface / Q000235:genetics*; D043562:Receptors, G-Protein-Coupled; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015534:Trans-Activators / Q000235:genetics*; D014162:Transfection; D051176:beta Catenin
chemical_list: C495270:CTNNB1 protein, human; C495267:CTNNB1 protein, mouse; D003598:Cytoskeletal Proteins; C116884:LGR5 protein, human; D008164:Luminescent Proteins; D012333:RNA, Messenger; D011956:Receptors, Cell Surface; D043562:Receptors, G-Protein-Coupled; D015534:Trans-Activators; D051176:beta Catenin; D049452:Green Fluorescent Proteins