Overexpression of orphan G-protein-coupled receptor, Gpr49, in human hepatocellular carcinomas with beta-catenin mutations.
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.
Yamamoto
Yoshiya
Y
Pathology Division, National Cancer Center Research Institute, Tokyo, Japan. Third Department of Internal Medicine, Hokkaido University Faculty of Medicine, Sapporo, Japan.
Sakamoto
Michiie
M
Fujii
Gen
G
Tsuiji
Hitomi
H
Kenetaka
Kengo
K
Asaka
Masahiro
M
Hirohashi
Setsuo
S
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
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