基于“治未病”思想的癌痛消方防治大鼠诱导性肝癌的实验研究
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摘要
目的1.以不同浓度的二乙基亚硝胺(DEN)水溶液诱发肝癌大鼠模型,并通过成癌率及生存时间等指标,确定诱发肝癌大鼠模型的最佳浓度及时间。2.检测64ppm DEN诱导的肝癌大鼠模型在不同时间点Bax、Bcl-2、Survivin、Fas、FasL、Caspase-3等基因的表达情况,确定与肝癌形成有关的优势基因。3.通过分析癌痛消方(Aitongxiao major Prescription,ATXP)干预治疗后肝癌大鼠模型在不同时间点肝脏组织病理变化,及Bax、Bcl-2、Survivin、Fas、FasL、Caspase-3等细胞凋亡相关基因和蛋白的表达变化和原位细胞凋亡情况,探讨其防治原发性肝癌的机制。
方法1.SPF级雄性Wistar大鼠96只,随机分为4组,每组24只。各组动物分别以含DEN 40ppm、64ppm、80ppm的水溶液和纯净水饲养,自由饮用,连续16周。于实验第16周,各组动物随机取12只处死,取肝脏标本并进行HE染色,在光学显微镜下观察各组动物肝癌病理切片并统计成癌率。各组剩余的12只大鼠用于观察生存时间。2. Wistar雄性大鼠60只,随机分为造模组40只、正常对照组20只。造模组饲以含64ppmDEN的自来水,饲养16周后,改为饮用自来水；对照组自由饮用自来水。分别于4W、8W、12W、16W.18W随机取出造模组动物4只、对照组动物2只,断头处死,取肝组织进行病理及Bcl-2、Bax、Caspase-3、Survivin、 Fas/FasL等基因表达分析。3.雄性Wistar大鼠40只,分为预防组和模型对照组,每组20只；动物以64ppm DEN饮水饲养,连续16周后,改为自来水。同时,自诱癌之日起,预防组予以ATXP灌胃(0.2g/100g),1/日每周连续用药6d,停药1d修整；模型对照组给药周期为18w。分别在4、8、12、16、8w,每组随机取4只大鼠断头处死,取肝组织(阳性部位)进行HE染色,观察癌组织的病理变化,并通过RT-PCR、SABC等方法检测肝组织Bax、Bcl-2、Survivin、Fas、FasL、Caspase-3等基因和蛋白的表达,并采用TUNNEL法检测肝细胞原位凋亡情况。
结果1.动物饲养18w后,80ppm组成癌率为91.16%,64ppm组为83.33%,40ppm组为0;80ppm组22w病死率为33.33%,26w病死率为100%,而64ppm组大鼠第22w病死率为0,26w病死率为16.67%,第30w病死率为100%;40ppm组在第30w病死率为16.67%。80ppm组和64ppm组成癌率,无显著性差异(p>0.05)；但在生存期方面,前者明显延长(p<0.05)。
2.各时间点病理检测结果显示,大鼠肝组织存在肝损伤和病理损伤,经历肝脏炎症→脂肪病变→肝纤维化→肝硬化→肝癌的病程发展过程,同HBV病毒感染的病理一致。DEN处理的大鼠,各时间点肝组织中Bax、Bcl-2基因持续高表达,Survivin、Fas基因仅在第8w高表达；Fasl基因在第8w、12w、18w匀高表达；Casepase处于低表达或不表达水平。
3、RT-PCR结果：ATX干预过程可以全程下调survivin、Bcl-2基因的表达,上调casepase基因的表达,Bax仅在12w表达上调,Fas和Fasl在4w表达上调,其余时间点变化不明显
4.免疫组化结果：survivin、casepase-3. Fas/Fasl、Bax、Bcl-2蛋白表达和基因表达一致；对照组survivin在16w、18w表达明显。casepase-3蛋白在整个诱癌过程均表达较少；Bcl-2蛋白在诱癌早期就即有表达,在诱癌过程呈现持续高表达,18w达峰值；而Bax、Fas/Fasl蛋白在第8w表达量最高；预防组抑制凋亡基因survivin和Bcl-2在整个观察时间点表达均较对照组表达降低(p<0.05)；casepase-3和Bax蛋白在整个观察时间点表达均明显升高(p<0.05)；Fas、Fasl蛋白表达量在4w较对照组明显升高(p<0.0)。
5.TUNEL结果：阴性对照组各时间点未见凋亡细胞；模型组在4w、8w.12w未见凋亡细胞,16w、18w存在少量凋亡细胞；预防组在4w未观察到凋亡细胞,8w、12w有少量凋亡细胞,而16w到18w凋亡细胞数量显著增多,细胞凋亡指数增高。与模型组相比,有显著性差异(P<0.01)
结论1.64ppmDEN是一个诱癌用于药物疗效评价的大鼠肝癌模型较理想的条件。
2.DEN诱癌整个过程是以抑凋亡基因表达上调、促凋亡基因表达下调过程,提示肝癌诱导是一个细胞增殖活跃、凋亡相关基因受到抑制的过程。
3.ATX防治肝癌是通过下调凋亡抑制因子Bcl-2、survivin,上调凋亡因子casepase-3的表达,促进细胞凋亡,来实现抗癌作用的。
OBJECTIVE:1. To observe the cancer rate and survival time of rats and confirm the optimal concentration of DEN to induce cancer, after liver cancer in rats was induced by free-drinking with different concentrations of two diethylnitrosamine (DEN) water solutions.2. To identify protogene related to hepatocarcinogenesis by observing expression of Bax, Bcl-2, Survivin, Fas, FasL and Caspase-3mRNA induced by64ppm DEN in rats at different time.3. To discuss the mechanism of prevention and treatment of primary hepatic carcinoma from the pathological changes of liver tissue of rats induced by ATXP (Aitongxiao major Prescription) intervention at different time, expressional changes of relative cell apoptosis genes (gene and protein), such as Bax, Bcl-2, Survivin, Fas, FasL, Caspase-3and the in-situ cell apoptosis.
METHODS:1.96SPF male Wistar rats were randomly divided into4groups (n=24). Each group was fed freely with water containing DEN40ppm,64ppm,80ppm and purified water respectively for16weeks. In the16th week of the experiment,12rats in each group were randomly killed to take out livers to make specimens with HE staining, whose pathology and cancer-generating rate were observed under the optical microscope. The rest rats in each group were used to observe survival time.2.60male Wistar rats were randomly divided into model group (n=40) and control group (n=20). The model group was fed freely with running water containing DEN64ppm for16weeks and then running water while the control group just with running water.4rats in model group and2in control group in the4th,8th,12th,16th and18th week respectively were randomly decapitated to take out liver tissues to observe the pathology and to detect gene expression of Bcl-2, Bax, Caspase-3, Survivin and Fas/FasL through RT-PCR.3.40male Wistar rats, randomly divided into prevention group and model control group on average, were fed with drinking water containing DEN64ppm for16weeks and then with running water. From the cancer-induced day, prevention group was irrigated with ATXP (0.2g/100g), one time per day, continuous administration for6days in a week with a course of18weeks.4rats in the4th,8th,12th,16th and18th week respectively were randomly decapitated to take out liver tissues (passive part). The expressions of Bax, Bcl-2, Survivin, Fas, FasL, Caspase-3mRNA and the protein in liver tissues were detected through HE staining pathological observation, RT-PCR and SABC methods. The condition of liver cell apoptosis was inspected through TUNNEL method.
RESULTS:The cancer induction rate in the18th week was91.16%in the80ppm group,83.33%in the60ppm group and0in the40ppm group; in the80ppm group, death occurred in the22th week (4rats died) and at the26th week the death rate was100%. While in the64ppm group, rats began to die in the25th week and mortality was100%in the30th week; in the40ppm group, fatality rate was16.67%in the30th week. In terms of cancer rate, there was no obvious difference (P>0.05) between the80ppm group and the64ppm group. However, in the aspect of survival time, the former group was significantly longer than the later (p<0.05).
2. Pathological analysis of the rats indicated hepatic damage occurred all the time. The pathological damage involved inflammation of the liver, fat lesions, hepatic fibrosis, liver cirrhosis and liver cancer, the same as the pathological mechanism of HBV infection. Over-expression of Bax, Bcl-2existed in the DEN carcinogenesis rats all the time, while Survivin, FAS just occurred in the8th week; over-expression of Fasl appeared in the8th,12th and18th week; Casepase slightly expressed or did not express.
Results of RT-PCR:The intervention process of ATX can lower the expression of survivin and Bcl-2, up-regulate the expression of casepase all the time, up-regulate Bax only at the12th week and Fas, Fasl at the4th week, with no obvious up-regulation in the rest of the time.
4.1mmunohistochemical results:protein and gene expressions of survivin, casepase-3, Fas/Fasl, Bax, Bcl-2are consistent; Survivin expressed clearly in16w,18w and Casepase-3proteins less expressed in the whole process of cancer inducing in control group; The Bcl-2protein expressed in the early period of inducing cancer, present continuous high expression in process induced carcino-ma,18w to spike; While Bax, Fas/Fasl protein expression in8w quantity highest; Prevention grou-p of survivin apoptosis gene and the Bcl-2during the whole observation time point expressed lower than control group, P<0.05; Casepase-3and Bax protein expression were significantly higher during the whole observation time point, P<0.05; Fas, Fasl protein expression increased more significantly than those of control group in the4w, P<0.01).
5. TUNEL results:negative control group did not see apoptotic cells in each time point; model group in the4w and8w,12w no apoptotic cells,16w,18w visible small amounts of fluorescence, sugge-sting a small amount of apoptosis cells; Prevention group in4w no fluorescence,8w,12w a small amount of fluorescent,16w,18w fluorescence intensity increased, cell apoptosis quantity become more, the highest cell apoptosis index,16w,18w apoptosis significantly compared with model group, with significant difference(P<0.01).
CONCLUSION:1. DEN carcinogenesis with a concentration of64ppm is an ideal hepatocellular carcinoma model in rats which is used for drug effectiveness evaluation.
2. The whole process of DEN carcinogenesis prompts the activeness of cell proliferation and the apoptosis reduction through the expression of apoptosis gene inhibition and the expression of apoptosis promoting gene during the carcinogenesis process.
3. ATXP prevention and treatment of liver cancer promotes cell apoptosis to fulfill its antitumous effect by means of down-regulating the Bcl-2and survivin and up-regulating the expression of casepase-3.
方法1.SPF级雄性Wistar大鼠96只,随机分为4组,每组24只。各组动物分别以含DEN 40ppm、64ppm、80ppm的水溶液和纯净水饲养,自由饮用,连续16周。于实验第16周,各组动物随机取12只处死,取肝脏标本并进行HE染色,在光学显微镜下观察各组动物肝癌病理切片并统计成癌率。各组剩余的12只大鼠用于观察生存时间。2. Wistar雄性大鼠60只,随机分为造模组40只、正常对照组20只。造模组饲以含64ppmDEN的自来水,饲养16周后,改为饮用自来水；对照组自由饮用自来水。分别于4W、8W、12W、16W.18W随机取出造模组动物4只、对照组动物2只,断头处死,取肝组织进行病理及Bcl-2、Bax、Caspase-3、Survivin、 Fas/FasL等基因表达分析。3.雄性Wistar大鼠40只,分为预防组和模型对照组,每组20只；动物以64ppm DEN饮水饲养,连续16周后,改为自来水。同时,自诱癌之日起,预防组予以ATXP灌胃(0.2g/100g),1/日每周连续用药6d,停药1d修整；模型对照组给药周期为18w。分别在4、8、12、16、8w,每组随机取4只大鼠断头处死,取肝组织(阳性部位)进行HE染色,观察癌组织的病理变化,并通过RT-PCR、SABC等方法检测肝组织Bax、Bcl-2、Survivin、Fas、FasL、Caspase-3等基因和蛋白的表达,并采用TUNNEL法检测肝细胞原位凋亡情况。
结果1.动物饲养18w后,80ppm组成癌率为91.16%,64ppm组为83.33%,40ppm组为0;80ppm组22w病死率为33.33%,26w病死率为100%,而64ppm组大鼠第22w病死率为0,26w病死率为16.67%,第30w病死率为100%;40ppm组在第30w病死率为16.67%。80ppm组和64ppm组成癌率,无显著性差异(p>0.05)；但在生存期方面,前者明显延长(p<0.05)。
2.各时间点病理检测结果显示,大鼠肝组织存在肝损伤和病理损伤,经历肝脏炎症→脂肪病变→肝纤维化→肝硬化→肝癌的病程发展过程,同HBV病毒感染的病理一致。DEN处理的大鼠,各时间点肝组织中Bax、Bcl-2基因持续高表达,Survivin、Fas基因仅在第8w高表达；Fasl基因在第8w、12w、18w匀高表达；Casepase处于低表达或不表达水平。
3、RT-PCR结果：ATX干预过程可以全程下调survivin、Bcl-2基因的表达,上调casepase基因的表达,Bax仅在12w表达上调,Fas和Fasl在4w表达上调,其余时间点变化不明显
4.免疫组化结果：survivin、casepase-3. Fas/Fasl、Bax、Bcl-2蛋白表达和基因表达一致；对照组survivin在16w、18w表达明显。casepase-3蛋白在整个诱癌过程均表达较少；Bcl-2蛋白在诱癌早期就即有表达,在诱癌过程呈现持续高表达,18w达峰值；而Bax、Fas/Fasl蛋白在第8w表达量最高；预防组抑制凋亡基因survivin和Bcl-2在整个观察时间点表达均较对照组表达降低(p<0.05)；casepase-3和Bax蛋白在整个观察时间点表达均明显升高(p<0.05)；Fas、Fasl蛋白表达量在4w较对照组明显升高(p<0.0)。
5.TUNEL结果：阴性对照组各时间点未见凋亡细胞；模型组在4w、8w.12w未见凋亡细胞,16w、18w存在少量凋亡细胞；预防组在4w未观察到凋亡细胞,8w、12w有少量凋亡细胞,而16w到18w凋亡细胞数量显著增多,细胞凋亡指数增高。与模型组相比,有显著性差异(P<0.01)
结论1.64ppmDEN是一个诱癌用于药物疗效评价的大鼠肝癌模型较理想的条件。
2.DEN诱癌整个过程是以抑凋亡基因表达上调、促凋亡基因表达下调过程,提示肝癌诱导是一个细胞增殖活跃、凋亡相关基因受到抑制的过程。
3.ATX防治肝癌是通过下调凋亡抑制因子Bcl-2、survivin,上调凋亡因子casepase-3的表达,促进细胞凋亡,来实现抗癌作用的。
OBJECTIVE:1. To observe the cancer rate and survival time of rats and confirm the optimal concentration of DEN to induce cancer, after liver cancer in rats was induced by free-drinking with different concentrations of two diethylnitrosamine (DEN) water solutions.2. To identify protogene related to hepatocarcinogenesis by observing expression of Bax, Bcl-2, Survivin, Fas, FasL and Caspase-3mRNA induced by64ppm DEN in rats at different time.3. To discuss the mechanism of prevention and treatment of primary hepatic carcinoma from the pathological changes of liver tissue of rats induced by ATXP (Aitongxiao major Prescription) intervention at different time, expressional changes of relative cell apoptosis genes (gene and protein), such as Bax, Bcl-2, Survivin, Fas, FasL, Caspase-3and the in-situ cell apoptosis.
METHODS:1.96SPF male Wistar rats were randomly divided into4groups (n=24). Each group was fed freely with water containing DEN40ppm,64ppm,80ppm and purified water respectively for16weeks. In the16th week of the experiment,12rats in each group were randomly killed to take out livers to make specimens with HE staining, whose pathology and cancer-generating rate were observed under the optical microscope. The rest rats in each group were used to observe survival time.2.60male Wistar rats were randomly divided into model group (n=40) and control group (n=20). The model group was fed freely with running water containing DEN64ppm for16weeks and then running water while the control group just with running water.4rats in model group and2in control group in the4th,8th,12th,16th and18th week respectively were randomly decapitated to take out liver tissues to observe the pathology and to detect gene expression of Bcl-2, Bax, Caspase-3, Survivin and Fas/FasL through RT-PCR.3.40male Wistar rats, randomly divided into prevention group and model control group on average, were fed with drinking water containing DEN64ppm for16weeks and then with running water. From the cancer-induced day, prevention group was irrigated with ATXP (0.2g/100g), one time per day, continuous administration for6days in a week with a course of18weeks.4rats in the4th,8th,12th,16th and18th week respectively were randomly decapitated to take out liver tissues (passive part). The expressions of Bax, Bcl-2, Survivin, Fas, FasL, Caspase-3mRNA and the protein in liver tissues were detected through HE staining pathological observation, RT-PCR and SABC methods. The condition of liver cell apoptosis was inspected through TUNNEL method.
RESULTS:The cancer induction rate in the18th week was91.16%in the80ppm group,83.33%in the60ppm group and0in the40ppm group; in the80ppm group, death occurred in the22th week (4rats died) and at the26th week the death rate was100%. While in the64ppm group, rats began to die in the25th week and mortality was100%in the30th week; in the40ppm group, fatality rate was16.67%in the30th week. In terms of cancer rate, there was no obvious difference (P>0.05) between the80ppm group and the64ppm group. However, in the aspect of survival time, the former group was significantly longer than the later (p<0.05).
2. Pathological analysis of the rats indicated hepatic damage occurred all the time. The pathological damage involved inflammation of the liver, fat lesions, hepatic fibrosis, liver cirrhosis and liver cancer, the same as the pathological mechanism of HBV infection. Over-expression of Bax, Bcl-2existed in the DEN carcinogenesis rats all the time, while Survivin, FAS just occurred in the8th week; over-expression of Fasl appeared in the8th,12th and18th week; Casepase slightly expressed or did not express.
Results of RT-PCR:The intervention process of ATX can lower the expression of survivin and Bcl-2, up-regulate the expression of casepase all the time, up-regulate Bax only at the12th week and Fas, Fasl at the4th week, with no obvious up-regulation in the rest of the time.
4.1mmunohistochemical results:protein and gene expressions of survivin, casepase-3, Fas/Fasl, Bax, Bcl-2are consistent; Survivin expressed clearly in16w,18w and Casepase-3proteins less expressed in the whole process of cancer inducing in control group; The Bcl-2protein expressed in the early period of inducing cancer, present continuous high expression in process induced carcino-ma,18w to spike; While Bax, Fas/Fasl protein expression in8w quantity highest; Prevention grou-p of survivin apoptosis gene and the Bcl-2during the whole observation time point expressed lower than control group, P<0.05; Casepase-3and Bax protein expression were significantly higher during the whole observation time point, P<0.05; Fas, Fasl protein expression increased more significantly than those of control group in the4w, P<0.01).
5. TUNEL results:negative control group did not see apoptotic cells in each time point; model group in the4w and8w,12w no apoptotic cells,16w,18w visible small amounts of fluorescence, sugge-sting a small amount of apoptosis cells; Prevention group in4w no fluorescence,8w,12w a small amount of fluorescent,16w,18w fluorescence intensity increased, cell apoptosis quantity become more, the highest cell apoptosis index,16w,18w apoptosis significantly compared with model group, with significant difference(P<0.01).
CONCLUSION:1. DEN carcinogenesis with a concentration of64ppm is an ideal hepatocellular carcinoma model in rats which is used for drug effectiveness evaluation.
2. The whole process of DEN carcinogenesis prompts the activeness of cell proliferation and the apoptosis reduction through the expression of apoptosis gene inhibition and the expression of apoptosis promoting gene during the carcinogenesis process.
3. ATXP prevention and treatment of liver cancer promotes cell apoptosis to fulfill its antitumous effect by means of down-regulating the Bcl-2and survivin and up-regulating the expression of casepase-3.
引文
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