Overexpression of orphan G-Protein-coupled receptor, Gpr49, in human hepatocellular carcinomas with β-catenin mutations
Overexpression of orphan G-Protein-coupled receptor, Gpr49, in human hepatocellular carcinomas with β-catenin mutations
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DOI：
10.1053/jhep.2003.50029
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发表时间：
2003-03-01
期刊：
影响因子：
13.5
通讯作者：
Hirohashi, S
中科院分区：
文献类型：
--
作者：
Yamamoto, Y;Sakamoto, M;Hirohashi, S
为了鉴定与肝细胞癌（HCC）发生和发展相关的基因，我们筛选了几种人HCC细胞系中差异表达的基因。其中，Gpr 49在PLC/PRF/5和HepG 2中表达上调。Gpr 49是糖蛋白激素受体亚家族的成员，该亚家族包括促甲状腺激素受体（TSHR）。然而，Gpr 49仍然是一个孤儿G蛋白偶联受体。通过实时定量逆转录聚合酶链反应（RT-PCR）分析，与相应的非癌肝组织相比，在38例HCC中的18例（47%）中观察到Gpr 49 mRNA的过表达（与相应的非癌肝组织相比增加>3倍）。在临床病理上，Gpr 49在β-catenin第3外显子突变的HCC中频繁表达（14/16例，87.5%）。此外，在培养的小鼠肝细胞中引入突变的β-连环蛋白引起Gpr 49小鼠同源物的上调。因此，Gpr 49可能是HCC中Wnt信号激活的靶基因。总之，尽管仍有许多未知数，但Gpr 49可能与β-连环蛋白突变的HCC的发展密切相关，并有可能成为HCC治疗的新靶点。
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.