The Wnt antagonist sFRP1 in colorectal tumorigenesis
The Wnt antagonist sFRP1 in colorectal tumorigenesis
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DOI：
10.1158/0008-5472.can-03-1346
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发表时间：
2004-02-01
期刊：
影响因子：
11.2
通讯作者：
Morton, DG
中科院分区：
文献类型：
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作者：
Caldwell, GM;Jones, C;Morton, DG
在一系列实体肿瘤中，8号染色体短臂的区域经常缺失，表明肿瘤抑制基因存在于这些位点上。在这项研究中，我们研究了Writ信号拮抗剂分泌卷曲相关蛋白（sFRP） 1作为c8p11.2位点的候选蛋白的特性。对10个结肠肿瘤的初步调查，通过8p11.2区域的分离短缺失，确定了三个链终止突变，都在编码半胱氨酸富域的第一个外显子内。这些肿瘤均未表现出微卫星不稳定性，表明错配修复基因功能完整。在其余7个肿瘤中保存的sFRP1等位基因在信号序列中都含有多态性的3个碱基插入，但在更广泛的研究中，没有发现这与结直肠癌的发展之间的关联。研究人员对sFRP1转录的表观遗传抑制进行了研究，并在另一组51例局部晚期结直肠癌中证实了启动子区域甲基化的增加。49例癌症中有40例（82%）存在高甲基化，而36例正常粘膜样本中只有11例（30%）存在高甲基化（P < 0.001）。通过实时PCR半定量分析51例癌症中37例的mRNA表达，发现与匹配的正常大肠黏膜相比，28例（76%）患者的sFRP1 mRNA表达下调。与肝脏和肺的原型形式相比，在结肠和许多其他组织中，sFRP1 mRNA的3'端也被发现是选择性剪接的，产生延长的COOH末端，这可能以组织特异性的方式影响其活性。观察到的sFRP1的失活和下调与其在结直肠癌发生过程中作为肿瘤抑制基因的作用是一致的。由于β -连环蛋白在大多数结直肠肿瘤中具有组成性活性，因此sFRP1不太可能在典型的Wnt反应途径中起作用。因此，我们认为sFRP1活性的降低或缺失允许非规范Wnt信号的转导，这有助于肿瘤的进展。
Regions of the short arm of chromosome 8 are deleted frequently in a range of solid tumors, indicating that tumor suppressor genes reside at these loci. In this study, we have examined the properties of the Writ signaling antagonist secreted frizzled-related protein (sFRP) 1 as a candidate for this role at c8p11.2. An initial survey of 10 colorectal tumors, selected by the presence of isolated short deletions of the 8p11.2 region, identified three chain-terminating mutations, all within the first exon, which encodes the cysteine-rich domain. None of these tumors exhibited microsatellite instability, indicating intact mismatch repair gene function. The preserved sFRP1 alleles in the remaining seven tumors each contained a polymorphic three-base insertion in the signal sequence, but in a broader study, no association was found between this and the development of colorectal cancer. Epigenetic inhibition of sFRP1 transcription was investigated, and increased methylation of the promotor region was demonstrated in an additional cohort of 51 locally advanced colorectal cancers. Hypermethylation was identified in 40 of 49 (82%) cancers and in only 11 of 36 (30%) matched normal mucosal samples (P < 0.001). Semiquantitative analysis, by real-time PCR, of mRNA expression in 37 of the same cohort of 51 cancers revealed that sFRP1 mRNA expression was down-regulated in 28 (76%) cases compared with matched normal large bowel mucosa. The 3' end of the sFRP1 mRNA also was found to be alternatively spliced, compared with the prototype liver and lung forms, in the colon and a number of other tissues, yielding an extended COOH terminus, which may influence its activity in a tissue-specific manner. The inactivation and down-regulation of sFRP1 observed are consistent with it acting as a tumor suppressor gene in colorectal carcinogenesis. Because beta-catenin is constitutively active in the majority of colorectal tumors, it is unlikely that sFRP1 can act in the canonical Wnt response pathway. Therefore, we propose that the reduced activity or absence of sFRP1 allows the transduction of noncanonical Wnt signals, which contribute to tumor progression.