地西他滨有效抑制前列腺癌PC3细胞移植瘤

Decitabine effectively inhibits the growth on castration-resistant prostate cancer PC3 xenograft

目的:观察DNA甲基转移酶1(DNMT1)抑制剂地西他滨(Decitabine)对前列腺癌裸鼠移植瘤的治疗作用,并探讨其机制。方法:通过PC3细胞系构建裸鼠去势抵抗性前列腺癌皮下移植瘤模型,当肿瘤体积为100 mm 3随机分成两组,分别为空白对照组[磷酸盐缓冲液(PBS)组]和药物处理组(Decitabine组)。每3 d测量肿瘤体积,并绘制肿瘤时间-体积生长曲线。免疫组织化学检测肿瘤组织中细胞核增殖抗原(Ki-67)、DNMT1和p21蛋白表达。组织芯片进行免疫组织化学染色并评分,检测DNMT1和p21表达及相关性。数据符合正态分布时采用t检验分析两样本之间差异,采用ANOVA分析多组间差异。数据不符合正态分布时,组间比较采用Manu-Whitney U检验。采用χ^(2)检验分析定性资料差异。结果:成功构建裸鼠前列腺癌PC3细胞系移植瘤模型。药物处理组和PBS组移植瘤终体积分别为(611.34±117.35)mm 3和(139.66±71.11)mm 3,差异有统计学意义(t=7.686,P<0.01)。免疫组织化学法检测肿瘤组织中Ki-67、DNMT1和p21蛋白表达的结果显示,药物处理组DNMT1和Ki-67表达显著低于PBS组,差异有统计学意义(t=7.686、12.820,P<0.01、P<0.01),而p21蛋白表达显著高于PBS组,两者差异有统计学意义(t=-2.890,P<0.05)。组织芯片结果显示在前列腺癌中DNMT1高表达,而p21低表达,两者之间存在线性关系(R2=0.638,P<0.01)。结论:DNMT1抑制剂Decitabine能够有效抑制趋势抵抗前列腺癌PC3细胞皮下移植瘤的生长,其机制可能通过抑制DNMT1、Ki-67和促进p21表达抑制肿瘤生长。

Objective To explore the therapeutic effect of DNA methyltransferase 1(DNMT1)inhibitor Decitabine on the prostate cancer PC3 xenografts,and explore the underlying mechanism.Methods The human prostate cancer PC3 xenograft models in nude mice were established.When the tumor volume was 100 mm3,it was randomly divided into two groups,namely the control group[phosphate buffer saline(PBS)]and the drug-treated group(Decitabine group,1 mg/kg).Tumor volumes were measured every three days,and tumor time-volume growth curves were plotted.Immunohistochemistry was used to detect the expression of proliferation cell nuclear antigen(Ki-67),DNMT1 and p21 in tumor tissues.The tissue microarray was stained and scored to detect the expression and correlation of DNMT1 and p21.When the data were in accordance with normal distribution,the differences between the two samples were analyzed by t-test,and the differences between multiple groups were analyzed by ANOVA.When the data did not conform to the normal distribution,the Manu-Whitney U test was used to compare the data between groups.The differences of qualitative data were analyzed byχ^(2) test.Use the Prism8.0 software to draw the picture.Results The xenograft tumor model of nude mice were successfully constructed.The average volumes of tumors in the drug group and PBS group were(611.34±117.35)mm3 and(139.66±71.11)mm3,respectively,and the difference was statistically significant(t=7.686,P<0.01).Immunohistochemical staining showed that the expression of Ki-67 and DNMT1 in decitabine groups were significantly reduced(t=7.686,12.820,P<0.01,P<0.01),while the expression of p21 increased significantly(t=-2.890,P<0.05).The microarray tissue showed that DNMT1 was highly expressed in prostate cancer,while p21 was lowly expressed,and there was a linear relationship between DNMT1 and p21(R2=0.638,P<0.01).Conclusion The DNMT1 inhibitor-Decitabine-can effectively inhibit the growth of xenografts of PC3 cells.Its mechanism may include inhibiting DNMT1 and Ki-67,and increasing p21 expression.