Gallbladder cancer (GBC) is relatively rare but has a high mortality rate. One candidate molecule which might be involved in GBC development is prostate stem cell antigen (PSCA), a glycosylphosphatidylinositol-anchored cell surface antigen with a tissue-specific pattern of expression in the epithelium of several organs, such as the prostate, stomach, bladder, and gallbladder. It is up-regulated in a number of cancers including prostate, urinary bladder, and pancreatic cancers, while it is down-regulated in esophageal and gastric cancers, suggesting that PSCA has an oncogenic activity in the former but a tumor suppressor activity in the latter. However, the precise function of PSCA and the regulatory mechanism for its expression in normal and cancer cells are yet to be determined. In this study, immunohistochemical analyses with a specific antibody revealed that PSCA is down-regulated in non-neoplastic gallbladder lesions such as cholesterolosis, cholecystolithiasis, and cholecystitis (9/17; 53%), and also in adenocarcinoma (40/44; 91%), a common neoplasm in gallbladder. Analyses of the DNA methylation status in the GBC cell lines by bisulfite-Pyrosequencing and a reporter assay for the PSCA promoter activity suggested that the down-regulation is explained, at least partly, by DNA methylation. Moreover, colony formation assay revealed that PSCA has cell-proliferation inhibition activity in the GBC cell lines, which was also observed in vivo. These lines of in vivo and in vitro evidence suggest that PSCA is acting as a tumor suppressor in GBC development.
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