Frequent epigenetic inactivation of SFRP genes and constitutive activation of Wnt signaling in gastric cancer
Frequent epigenetic inactivation of SFRP genes and constitutive activation of Wnt signaling in gastric cancer
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DOI：
10.1038/sj.onc.1210259
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发表时间：
2007-07-12
期刊：
影响因子：
8
通讯作者：
Shinomura, Y.
中科院分区：
文献类型：
--
作者：
Nojima, M.;Suzuki, H.;Shinomura, Y.
Wnt信号的激活与胃肿瘤的发生有关，尽管APC（结肠腺瘤性息肉病）、CTNNB 1（β-连环蛋白）和AXIN的突变在胃癌（GC）中的频率远低于结直肠癌。在本研究中，我们研究了Wnt信号的激活和分泌型卷曲相关蛋白（SFRP）家族基因在胃癌中表达的变化之间的关系。我们经常观察到细胞核β-连环蛋白积聚（13/15; 87%），并在大多数（12/16; 75%）GC细胞系中检测到β-连环蛋白的活性形式。SFRP 1、SFRP 2和SFRP 5的CpG甲基化依赖性沉默在GC细胞系中常见（SFRP 1，16/16，100%; SFRP 2，16/16，100%; SFRP 5，13/16，81%）和主要GC标本（SFRP 1，42/46，91%; SFRP 2，44/46，96%; SFRP 5，30/46，65%），用DNA甲基转移酶抑制剂5-氮杂-2 '-脱氧胞苷处理迅速恢复SFRP表达。SFRPs的异位表达下调T细胞因子/淋巴细胞增强因子的转录活性，抑制细胞生长，诱导胃癌细胞凋亡。全局表达分析显示，SFRP 2过表达抑制Wnt靶基因，并诱导GC细胞中与增殖、生长和凋亡相关的许多基因表达的变化。因此，似乎异常SFRP甲基化是GC中Wnt信号传导被激活的主要机制之一。
Activation of Wnt signaling has been implicated in gastric tumorigenesis, although mutations in APC (adenomatous polyposis coli), CTNNB1 (beta-catenin) and AXIN are seen much less frequently in gastric cancer (GC) than in colorectal cancer. In the present study, we investigated the relationship between activation of Wnt signaling and changes in the expression of secreted frizzled-related protein (SFRP) family genes in GC. We frequently observed nuclear beta-catenin accumulation (13/15; 87%) and detected the active form of beta-catenin in most (12/16; 75%) GC cell lines. CpG methylation-dependent silencing of SFRP1, SFRP2 and SFRP5 was frequently seen among GC cell lines (SFRP1, 16/16, 100%; SFRP2, 16/16, 100%; SFRP5, 13/16, 81%) and primary GC specimens (SFRP1, 42/46, 91%; SFRP2, 44/46, 96%; SFRP5, 30/46, 65%),and treatment with the DNA methyltransferase inhibitor 5-aza-2'-deoxycytidine rapidly restored SFRP expression. Ectopic expression of SFRPs downregulated T-cell factor/lymphocyte enhancer factor transcriptional activity, suppressed cell growth and induced apoptosis in GC cells. Analysis of global expression revealed that overexpression of SFRP2 repressed Wnt target genes and induced changes in the expression of numerous genes related to proliferation, growth and apoptosis in GC cells. It thus appears that aberrant SFRP methylation is one of the major mechanisms by which Wnt signaling is activated in GC.