Frequent silencing of protocadherin 8 by promoter methylation, a candidate tumor suppressor for human gastric cancer.

The cadherins are a family of cell surface glycoproteins responsible for cell adhesion which play an important role in cell morphology, contact inhibition and signal transduction during tumorigenesis. Protocadherin 8 (PCDH8), a member of the cadherin family, has been reported to act as a tumor suppressor involved in oncogenesis in breast cancer. In this study, we aimed to investigate the epigenetic inactivation of PCDH8 and its tumor suppressor function in gastric cancer. The expression of PCDH8 was markedly reduced or silenced in gastric cancer cell lines compared with normal gastric cells or tissues. Methylation of the PCDH8 gene promoter was observed in 100% (4/4) of cell lines and 55.38% (36/65) of the primary gastric cancer by methylation-specific PCR, but not in normal gastric mucosa (0/10). Methylated PCDH8 was significantly associated with lymph node metastasis in a logistic regression analysis. The demethylation reagent 5-aza-2'-deoxycytidine was able to restore or upregulate PCDH8 expression in gastric cancer cell lines. Ectopic expression of PCDH8 in silenced gastric cancer cells significantly inhibited cell migration and induced apoptosis. For the first time, our study demonstrates the epigenetic inactivation of PCDH8 by promoter methylation and its tumor suppressor function in human gastric cancer. Thus, PCDH8 could be identified as a candidate tumor suppressor in human gastric cancer.