Arisawa Tomiyasu, Tahara Tomomitsu, Shibata Tomoyuki, Nagasaka Mitsuo, Nakamura Masakatsu, Kamiya Yoshio, Fujita Hiroshi, Yoshioka Daisuke, Arima Yuko, Okubo Masaaki, Hirata Ichiro, Nakano Hiroshi
Department of Gatroenterology, Fujita Health University, School of Medicine, Toyoake 470-1192, Japan.
Oncol Rep. 2008 Jan;19(1):211-6.
Aberrant promoter methylation is an important mechanism for gene silencing. Inflammation-related reactive oxygens contribute to this CpG island methylation. The nuclear factor-erythroid 2-related factor 2 gene (Nrf2) is known to regulate the expression of detoxifying and antioxidant genes. We investigated the relationship between promoter polymorphisms of Nrf2 gene and the CpG island methylation in non-cancerous gastric mucosa. The study was performed in 85 subjects (46 without gastric malignancies, non-GC group, and 39 with gastric cancer, GC group). The promoter methylation status of p14(ARF), p16(INK4a) and p21(Waf1) genes was determined by methylation-specific-polymerase chain reaction. The Nrf2 gene genotypes were determined by the PCR-SSCP method. In the 85 subjects, CpG island methylation was found in 25.9% for p14, 15.3% for p16, none for p21. The frequency of the methylated genes was significantly higher in GC group than non-GC group (OR, 2.67; 95% CI, 1.10-6.49; p=0.029). In particular, the frequency of p16 gene methylation was much higher in GC group (p=0.0023). The Nrf2 -686/-684 G/G haplotype was positively associated and A/G haplotype was inversely associated with the development of CpG island methylation, especially p14 gene methylation (OR, 3.28; 95% CI, 1.26-8.59; p=0.015, and OR, 0.38; 95% CI, 0.15-0.96; p=0.040, respectively). In Helicobacter pylori (H. pylori) infected subjects, the number of -686/-684 G/G allele was positively correlated and that of A/G allele was inversely correlated to the methylation status, especially p14 methylation, by the adjusted analysis (OR, 2.90; 95% CI, 1.14-7.36; p=0.026, and OR, 0.33; 95% CI, 0.13-0.88; p=0.027, respectively). Our results suggested that the promoter polymorphisms of Nrf2 gene may affect the methylation status of tumor-related genes, especially the p14 gene, under the influence of H. pylori-induced gastric inflammation.
异常的启动子甲基化是基因沉默的重要机制。炎症相关的活性氧促成了这种CpG岛甲基化。已知核因子红细胞2相关因子2基因（Nrf2）可调节解毒和抗氧化基因的表达。我们研究了Nrf2基因启动子多态性与非癌性胃黏膜中CpG岛甲基化之间的关系。该研究在85名受试者中进行（46名无胃恶性肿瘤者，非胃癌组，以及39名胃癌患者，胃癌组）。通过甲基化特异性聚合酶链反应确定p14（ARF）、p16（INK4a）和p21（Waf1）基因的启动子甲基化状态。通过PCR-SSCP方法确定Nrf2基因的基因型。在这85名受试者中，p14的CpG岛甲基化率为25.9%，p16为15.3%，p21无甲基化。甲基化基因的频率在胃癌组显著高于非胃癌组（比值比，2.67；95%可信区间，1.10 - 6.49；p = 0.029）。特别是，p16基因甲基化的频率在胃癌组中更高（p = 0.0023）。Nrf2 -686/-684 G/G单倍型与CpG岛甲基化的发生呈正相关，A/G单倍型与CpG岛甲基化呈负相关，尤其是p14基因甲基化（比值比分别为3.28；95%可信区间，1.26 - 8.59；p = 0.015，以及比值比0.38；95%可信区间，0.15 - 0.96；p = 0.040）。在幽门螺杆菌（H. pylori）感染的受试者中，经校正分析，-686/-684 G/G等位基因的数量与甲基化状态呈正相关，A/G等位基因的数量与甲基化状态呈负相关，尤其是p14甲基化（比值比分别为2.90；95%可信区间，1.14 - 7.36；p = 0.026，以及比值比0.33；95%可信区间，0.13 - 0.88；p = 0.027）。我们的结果表明，在幽门螺杆菌诱导的胃炎症影响下，Nrf2基因的启动子多态性可能影响肿瘤相关基因的甲基化状态，尤其是p14基因。
