As_2O_3对人乳腺癌裸鼠移植瘤淋巴管新生的作用及其机制研究

Effect and mechanism of arsenic trioxide on lymphangiogenesis of transplan tation tumor model for human breast infiltrating duct carcinoma in nude mice

目的:研究三氧化二砷(Arsenict rioxide,As2O3)对人乳腺浸润导管癌裸鼠移植瘤淋巴管生成的作用及其可能机制。方法:建立人乳腺浸润导管癌裸鼠移植瘤模型,随机分成阴性对照组(NS)、阳性对照组(5-FU30mg/kg)、处理组1(As2O31.5mg/kg)和处理组2(As2O33.0mg/kg)。采用免疫组化法检测移植瘤组织中微淋巴管密度(Microlymphatics density,MLD)及VEGF-C,NF-κBp65和Her2的表达;半定量逆转录PCR(RT-PCR)检测VEGF-CmRNA的表达。结果:两处理组癌组织中MLD低于阴性和阳性对照组(P<0.01),处理组2癌组织MLD低于处理组1(P<0.05)。对照组中VEGF-C表达高于两处理组(P<0.01),处理组1高于处理组2(P<0.05);VEGF-CmRNA的表达与其蛋白表达一致。各组中p65与Her2的表达与VEGF-CmRNA的表达呈正相关(r=0.782和r=0.848)。结论:As2O3对人乳腺癌裸鼠移植瘤淋巴管新生具有抑制作用;通过抑制p65和Her2的表达,从而降低VEGF-CmRNA的转录水平是其可能的作用机制。

Objective：To investigate the antitumor lymphangiogenesis activity and mechanism of arsenic trioxide on transplantation tumor model for human breast infiltrating duct carcinoma in nude mice. Methods： The mice bearing tumor were randomly divided into 4 groups-negative control, positive control, experiment group 1 and 2, which were injected into a tail vein with sodium chloride, 5-Fluorouracil（30 mg/kg） and arsenic trioxide （1.5 mg/kg or 3.0 mg/kg） for 7 days respectively. The intratumoral microlymphatics density （MLD） and expressions of vascular endothelial growth factor C（VEGF-C）, nuclear factor kappa-B P65,and Her2 protein were evaluated by immunohistochmistry methods. Reverse transcription-PCR was used to detect the expression of VEGF-C mRNA. Results： The tumors in arsenic trioxide groups showed significantly lower MLD than those in control groups（P〈0.01）, and those in experimental group 2 were lower than those in experimental group 1（P〈0.05）.However, the expressions of VEGF-C in tumors of control groups were significantly higher than arsenic groups（P〈0.01）, and those in experimental group 1 were higher than those in experimental group 2（P〈0.05）,which were the same as VEGF-C mRNA in tendency. The expressions of P65 and Her2 in all groups were positively correlative with VEGF-C mRNA, with correlation coefficients of 0.782 and 0.848. Conclusion： Arsenic trioxide has obvious antitumor lymphangio genesis activity against transplantation tumor model for human breast infiltrating duct carcinoma in nude mice. Inhibiting the expression of P65 and Her2 and then down-regulating transcription of VEGF-C mRNA maybe its mechanism.