Frequent epigenetic inactivation of secreted frizzled-related protein 2 (SFRP2) by promoter methylation in human gastric cancer.
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 (P<0.01). 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.
Cheng
Y Y
YY
Institute of Digestive Disease, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, China.
Yu
J
J
Wong
Y P
YP
Man
E P S
EP
To
K F
KF
Jin
V X
VX
Li
J
J
Tao
Q
Q
Sung
J J Y
JJ
Chan
F K L
FK
Leung
W K
WK
D048868:Adaptor Proteins, Signal Transducing; D000230:Adenocarcinoma / Q000235:genetics / Q000378:metabolism; D000818:Animals; D017209:Apoptosis; D001374:Azacitidine; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D019175:DNA Methylation; D017931:DNA Primers / Q000737:chemistry; D044127:Epigenesis, Genetic; D005136:Eye Proteins / Q000235:genetics / Q000378:metabolism; D005434:Flow Cytometry; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D011401:Promoter Regions, Genetic; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D013274:Stomach Neoplasms / Q000235:genetics* / Q000378:metabolism; D000094742:Secreted Frizzled-Related Proteins
D048868:Adaptor Proteins, Signal Transducing; D001374:Azacitidine; D017931:DNA Primers; D005136:Eye Proteins; D036341:Intercellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D011518:Proto-Oncogene Proteins; C117636:SFRP1 protein, human; D000094742:Secreted Frizzled-Related Proteins; C109618:SFRP2 protein, human; C118723:SFRP4 protein, human; C118511:SFRP5 protein, human