Department of Biochemistry, School of Medicine, Shiraz University of Medical Sciences, Zand Street, Shiraz, Iran.
Mol Biol Rep. 2012 May;39(5):6171-8. doi: 10.1007/s11033-011-1434-6. Epub 2011 Dec 30.
The WNT signaling is deregulated in most human colorectal cancers (CRC). Promoter methylation has been proposed as an alternative mechanism to inactivate genes in tumors. To gain insight into the methylation silencing of the WNT pathway during colorectal carcinogenesis, we examined the aberrant methylation profile of four genes, APC, Axin1, Axin2, and GSK3β in an unselected series of 112 sporadic colorectal tumors by methylation specific PCR. It has been suggested that the Axin2 C148T SNP is associated with the risk of developing certain types of cancers. To assess the contribution of Axin2 SNP to CRC susceptibility, we examined the Axin2 C148T genotype in CRC patients and 170 healthy controls by PCR-RFLP. The frequency of CRCs with at least one gene methylated was 18.75%. Promoter methylation of Axin2 and APC genes was detected in 7.1 and 11.9% of tumors, respectively. No aberrant methylation was found in Gsk3β and Axin1 gene in these tumor series. The methylation status of APC had no significant association with clinical parameters. But, promoter methylation of Axin2 was sex-related, occurring more frequently in females (P = 0.002). The frequency of Axin2 C148T genotypes were similar in patients and controls. Moreover, we observed no association between the Axin2 SNP and risk of CRC in patients stratified by age, sex, and smoking status. However, the heterozygote CT genotype was associated with a reduced CRC risk in distal patients compared with proximal patients (OR = 0.3; 95% CI 0.1-0.9, P = 0.04). Our findings indicate that Axin1 and GSK3β methylation play a minor role in colorectal carcinogenesis.
WNT 信号在大多数人类结直肠癌（CRC）中失调。启动子甲基化已被提议作为一种替代机制，用于失活肿瘤中的基因。为了深入了解结直肠发生过程中 WNT 通路的甲基化沉默，我们通过甲基化特异性 PCR 检查了 112 例散发性结直肠肿瘤中四个基因 APC、Axin1、Axin2 和 GSK3β 的异常甲基化谱。已经有人提出，Axin2 C148T SNP 与某些类型癌症的发病风险有关。为了评估 Axin2 SNP 对 CRC 易感性的贡献，我们通过 PCR-RFLP 检查了 CRC 患者和 170 名健康对照者的 Axin2 C148T 基因型。至少有一个基因甲基化的 CRC 频率为 18.75%。Axin2 和 APC 基因的启动子甲基化分别在 7.1%和 11.9%的肿瘤中检测到。在这些肿瘤系列中，Gsk3β 和 Axin1 基因没有异常甲基化。APC 的甲基化状态与临床参数没有显著相关性。但是，Axin2 的启动子甲基化与性别有关，在女性中更常见（P=0.002）。Axin2 C148T 基因型的频率在患者和对照组中相似。此外，我们观察到，在按年龄、性别和吸烟状况分层的患者中，Axin2 SNP 与 CRC 风险之间没有关联。然而，与近端患者相比，杂合子 CT 基因型与远端患者的 CRC 风险降低相关（OR=0.3；95%CI 0.1-0.9，P=0.04）。我们的研究结果表明，Axin1 和 GSK3β 甲基化在结直肠发生中起次要作用。
