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目的探讨二甲基肼(DMH)诱导小鼠大肠癌模型中5-脱氧杂氮胞苷(5-aza-dC)预防肿瘤发生的作用机制。方法80只ICR小鼠分为4组,每组20只。包括空白对照组、5-aza-dC对照组、DMH诱癌组和5-aza-dC干预组。处理20周后观察其对肿瘤发生率的影响。实时定量PCR检测Dnmt1、Dnmt3a、Dnmt3b基因和抑癌基因p27~(Kipl)的表达。结果通过5-aza-dC干预能使诱导的大肠肿瘤发生率从95%降至35%,肿瘤数目(个)由9.43±4.21减少到3.98±2.95,肿瘤最大直径(单位:mm)由6.43±5.12缩小到3.44±2.11,差异有统计学意义(P<0.05)。实时定量PCR检测发现肿瘤组织中存在Dnmt1和Dnmt3b的高表达,而p27~(Kipl)的表达量降低。5-aza-dC可以通过抑制甲基化酶活性,防止p27~(Kipl)基因的高甲基化失活。结论5-aza-dC可以显著降低DMH诱发小鼠大肠癌的发生率,阻止抑癌基因的高甲基化失活可能是5-aza-dC预防肿瘤的重要机制。
Objective To investigate the mechanism of 5-aza-dC in the prevention of tumorigenesis in mouse model of colorectal cancer induced by dimethylhydrazine (DMH). Methods 80 ICR mice were divided into 4 groups with 20 mice in each group. Including the blank control group, 5-aza-dC control group, DMH induced cancer group and 5-aza-dC intervention group. After 20 weeks of treatment, the effect on tumor incidence was observed. Real-time quantitative PCR was used to detect the expression of Dnmt1, Dnmt3a, Dnmt3b and tumor suppressor gene p27 Kipl. Results The incidence of colorectal cancer was reduced from 95% to 35% by 5-aza-dC intervention. The number of tumors decreased from 9.43 ± 4.21 to 3.98 ± 2.95. The maximum diameter of tumor from 6.43 ± 5.12 reduced to 3.44 ± 2.11, the difference was statistically significant (P <0.05). Real-time quantitative PCR showed that there was high expression of Dnmt1 and Dnmt3b in tumor tissues, while the expression of p27 Kipl was decreased. 5-aza-dC can prevent hypermethylation of p27 Kipl gene inactivation by inhibiting methylase activity. Conclusions 5-aza-dC can significantly reduce the incidence of colorectal cancer in DMH-induced mice and prevent the inactivation of hypermethylation of tumor suppressor genes may be an important mechanism of 5-aza-dC in preventing tumors.