表观遗传修饰肿瘤细胞疫苗皮下注射对仓鼠胰腺癌的抗肿瘤效应

Anti-tumor effects of tumor cell vaccine by epigenetic modification on pancreatic cancer of hamster

目的观察表观遗传修饰的肿瘤细胞疫苗皮下注射后对仓鼠胰腺癌皮下移植瘤的抗肿瘤效应。方法通过皮下注射N-亚硝基双-2-氧丙基建立仓鼠胰腺癌模型,将仓鼠胰腺肿瘤取出、切碎,取0.5 cm×0.5 cm×0.5 cm的肿瘤组织移植在健康仓鼠的腹股沟皮下,建立仓鼠皮下移植瘤模型。采用组蛋白去乙酰化酶抑制剂和甲基化转移酶抑制剂表观遗传修饰胰腺癌PANC-1细胞,构建肿瘤细胞疫苗,同时构建对照细胞疫苗。将12只荷移植瘤仓鼠随机分为疫苗注射组和对照组(各6只),疫苗注射组皮下注射肿瘤细胞疫苗,对照组皮下注射对照细胞疫苗。荷移植瘤仓鼠于第4周统一处死,观察两组肿瘤生长情况及瘤组织中环氧合酶2(COX-2)、5脂氧合酶(5-LOX)、半乳凝素1(GAL-1)、半乳凝素3(GAL-3)、主要组织相容性复合体(MHC)Ⅰ、MHCⅡ的表达变化。结果疫苗注射组移植瘤大小随时间延长呈递减趋势,对照组移植瘤大小随时间延长呈递增趋势;疫苗治疗组肿瘤大小平均为0.39 cm、对照组为0.82 cm,两组相比,P<0.05;疫苗注射组移植瘤组织中COX-2、5-LOX、GAL-1、GAL-3的表达较对照组降低,而MHCⅠ、MHCⅡ表达较对照组升高,两组相比,P均<0.01。结论表观遗传修饰的肿瘤细胞疫苗皮下注射能有效延缓仓鼠胰腺癌移植瘤的生长,降低移植瘤组织中COX-2、5-LOX、GAL-1、GAL-3的表达,上调MHCⅠ、MHCⅡ的表达。

Objective To observe the anti-tumor effects of tumor cell vaccine by epigenetic modification on pancreatic cancer of hamster through subcutaneous injection. Methods The hamster pancreatic cancer models were set up by subcutaneous injection of N-nitrosobis-2-oxopropylamin. We removed the pancreatic tumor,chopped,and took 0. 5 cm × 0. 5 cm× 0. 5 cm tumor tissue to transplant into groin skin of healthy hamsters,and then the hamster subcutaneous transplanted tumor models were set up. In addition,PANC-1 cells were treated by histone deacetylase inhibitors and methyl transferase inhibitor epigenetic modification to make the tumor cell vaccine. Meanwhile,the control cell vaccine was set up. Twelve hamster pancreatic cancer xenografts were divided into two groups,6 in each group： the vaccinated group and the control group which were respectively treated with tumor cell vaccine and control cell vaccine by subcutaneous injection. The tumor growth and the expression of cyclooxyg enase-2（ COX-2）,5-LOX,GAL-1,GAL-3,MHC Ⅰ and MHC Ⅱ of the two groups were observed. Results In the vaccinated group,the tumor size（ mean size 0. 39 cm） was decreased with the prolonged time,but in the control group,the tumor size（ mean size 0. 82 cm） was increased with the prolonged time.Tumor size was statistical different between the two groups（ P〈0. 05）. The expression of COX-2,5-LOX,GAL-1 and GAL-3 was lower in the vaccinated group as compared with that of the control group,and MHC Ⅰ,MHC Ⅱ expression was higher than that of the control group,the difference was statistically significant（ all P〈0. 01）. Conclusion The epigenetic modification tumor vaccine can effectively delay the growth of transplanted tumor,reduce the expression of COX-2,5-LOX,GAL-1 and GAL-3,and up-regulate the expression of MHC Ⅰ and MHC Ⅱ.