Frequent epigenetic inactivation of DICKKOPF family genes in human gastrointestinal tumors
Frequent epigenetic inactivation of DICKKOPF family genes in human gastrointestinal tumors
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DOI：
10.1093/carcin/bgm178
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发表时间：
2007-12-01
期刊：
影响因子：
4.7
通讯作者：
Shinomura, Yasuhisa
中科院分区：
文献类型：
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作者：
Sato, Hironobu;Suzuki, Hiromu;Shinomura, Yasuhisa
Wnt信号传导的激活与肿瘤发生有关，并且在各种癌症中检测到Wnt拮抗剂基因的表观遗传沉默。在本研究中，我们研究了DICKKOPF（DKK）家族基因在胃肠道癌细胞系中的表达和甲基化。我们发现所有已知的DKK基因在结直肠癌（CRC）细胞中频繁地沉默（DKK 1，3/9，33%; DKK 2，89，89%; DKK 3，5/9，56%和DKK 4，5/9，56%），但在正常结肠粘膜中不沉默。DKK 1、DKK-2和DKK-3具有5' CpG岛，并且在表达和甲基化之间显示出负相关。在胃癌（GC）细胞系中也经常观察到DKK甲基化（DKK 1，6/16，38%; DKK 2，15/16，94%和DKK 3，10/16，63%），但在肝细胞癌和胰腺癌细胞系中较少观察到。DKK在原发性CRC（DKK 1，7/58，12%; DKK 2，45/58，78%和DKK 3，12/58，21%）和GC（DKK 1，15/31，48%; DKK 2，26/31，84%和DKK 3，12/31，39%）中也经常甲基化。在CTNNB 1或APC突变的背景下，Dickkopfs（Dkks）是比分泌的卷曲相关蛋白更不有效的Wnt信号传导抑制剂，尽管Dkks的过表达抑制了具有此类突变的CRC细胞的集落形成。我们的研究结果表明，DKK是胃肠道肿瘤中表观遗传沉默的常见靶点，DKK的缺失可能通过β-连环蛋白/T细胞因子非依赖性机制促进肿瘤发生。
Activation of Wnt signaling has been implicated in tumorigenesis, and epigenetic silencing of Wnt antagonist genes has been detected in various cancers. In the present study, we examined the expression and methylation of DICKKOPF (DKK) family genes in gastrointestinal cancer cell lines. We found that all known DKK genes were frequently silenced in colorectal cancer (CRC) cells (DKK1, 3/9, 33%; DKK2, 8/9, 89%; DKK3, 5/9, 56% and DKK4, 5/9, 56%), but not in normal colon mucosa. DKK1, -2 and -3 have 5' CpG islands, and show an inverse relation between expression and methylation. DKK methylation also was frequently observed in gastric cancer (GC) cell lines (DKK1, 6/16, 38%; DKK2, 15/16, 94% and DKK3, 10/16, 63%), but was seen less frequently in hepatocellular carcinoma and pancreatic cancer cell lines. DKKs also were frequently methylated in primary CRCs (DKK1, 7/58, 12%; DKK2, 45/58, 78% and DKK3, 12/58, 21%) and GCs (DKK1, 15/31, 48%; DKK2, 26/31, 84% and DKK3, 12/31, 39%). Against a background of CTNNB1 or APC mutations, Dickkopfs (Dkks) were less effective inhibitors of Wnt signaling than secreted frizzled-related proteins, though over-expression of Dkks suppressed colony formation of CRC cells with such mutations. Our results demonstrate that DKKs are frequent targets of epigenetic silencing in gastrointestinal tumors, and that loss of DKKs may facilitate tumorigenesis through beta-catenin/T-cell factor-independent mechanisms.