Frequent epigenetic inactivation of secreted frizzled-related protein 2 (SFRP2) by promoter methylation in human gastric cancer

Abstract

The role of secreted frizzled-related protein (SFRP) genes in gastric cancer remains largely unknown. We determined the frequency and functional significance of SFRPs hypermethylation in human gastric cancer. The expression and methylation status of four SFRP members (SFRP1, 2, 4, and 5) in primary gastric cancer samples was screened. The biological effects of SFRP were analysed by flow cytometry, cell viability assay and in vivo tumour growth in nude mice. Among the four SFRPs, only SFRP2 was significantly downregulated in gastric cancer as compared to adjacent non-cancer samples (Po0.01). Promoter hypermethylation of SFRP2 was detected in 73.3% primary gastric cancer tissues, 37.5% of samples showing intestinal metaplasia and 20% adjacent normal gastric tissues. Bisulphite DNA sequencing confirmed the densely methylated SFRP2 promoter region. Demethylation treatment restored the expression of SFRP2 in gastric cancer cell lines. Forced expression of SFRP2 induced cell apoptosis, inhibited proliferation of gastric cancer cells and suppressed tumour growth in vivo. Moreover, methylated SFRP2 was detected in 66.7% of serum samples from cancer patients but not in normal controls. In conclusion, epigenetic inactivation of SFRP2 is a common and early event contributing to gastric carcinogenesis and may be a potential biomarker for gastric cancer.

Low expression of secreted frizzled-related protein 2 and nuclear accumulation of β-catenin in aggressive nonfunctioning pituitary adenoma

“…These findings are consistent with those from other studies, which also reported a similar inverse correlation between the above proteins in endometrial, ovarian and breast cancer (37,38). The present findings, together with those from previous studies, suggest that sFRP2 may act as a tumor suppressor through its interaction with the Wnt canonical signaling pathway by modulating the cellular cytosolic pool of β-catenin (22).…”

Fibulin 1 is downregulated through promoter hypermethylation in gastric cancer

“…Over the past several years, many TSGs have been found to be epigenetically inactivated in gastric cancer, indicating that epigenetic silencing of TSGs is one of the major molecular alterations in the process of gastric carcinogenesis To et al, 2002;Choi and Wu, 2005;Chan and Rashid, 2006;Sato and Meltzer, 2006;Cheng et al, 2007). In this study, FBLN1 was identified as another candidate TSG whose inactivation may contribute to gastric carcinogenesis.…”

“…Genomic DNA was bisulphite-treated with the Zymo DNA Modification Kit (Zymo Research, Orange, CA, USA) according to the protocol provided. Methylation-specific PCR was carried out for 40 cycles with annealing temperature at 621C, as described earlier (Cheng et al, 2007). Methylation-specific primers were FBLN1M-F: 5 0 -attaggagattcgcggtttc and FBLN1M-R: 5 0 -gctccataaacgacgaacg, and the unmethylation-specific primers were FBLN1U-F: 5 0 -gattaggagatttgtggttttg and FBLN1U-R: 5 0 -cacactccataaacaacaaaca.…”

“…Moreover, promoter hypermethylation of tumour-related genes has also been proposed as a novel biomarker for detecting cancer and predicting prognosis (Jones and Baylin, 2007). We and others have shown earlier that many tumour-related genes were frequently silenced through promoter hypermethylation in gastric carcinoma as well as pre-malignant gastric lesions (Leung et al, 2001; Lee et al, 2002;To et al, 2002;Chan et al, 2004;Choi and Wu, 2005;Chan and Rashid, 2006;Sato and Meltzer, 2006;Cheng et al, 2007;Ushijima, 2007;Vogiatzi et al, 2007), suggesting that promoter hypermethylation can be utilised as biomarkers for early detection of gastric cancer.…”

Diagnostic and prognostic value of the methylation status of secreted frizzled-related protein 2 in colorectal cancer

“…e bisul temodi ed DNA was subjected to methylation-speci c polymerase chain reaction (MS-PCR) for detection of the methylation status of the CpG-rich region (-219 to -81 relative to the transcription start site) in the SFRP2 promoter, as described previously [27].…”