消癌解毒方对H22荷瘤小鼠和人肝癌SMMC-7721细胞的影响及机制研究
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摘要
目的：通过对H22荷瘤小鼠移植瘤基因表达谱的检测,发现更多与消癌解毒方治疗作用相关的信号通路和细胞因子。通过细胞实验,从细胞分了水平进一步探讨消癌解毒方抗癌机制。
方法：动物实验部分,H22荷瘤小鼠随机分为空白对照组,消癌解毒方低、中、高剂量组和顺铂组。应用基因芯片技术,检测各组H22荷瘤小鼠肿瘤组织的差异表达基因；应用Gene Ontology (GO)和pathway分析,找出与消癌解毒方抗癌机制相关的信号通路和基因；并用实时定量PCR法(Realtime-PCR)验证MMP9、MMP12、TIMP2、VEGF和TGFβ等基因的表达。细胞实验部分,以低、中、高剂量组的消癌解毒方含药血清培养人肝癌SMMC-7721细胞,噻唑蓝还原法(MTT)检测消癌解毒方对肝癌细胞的抑制作用；电镜观察细胞的凋亡形态；膜联蛋白A5一绿色荧光素/碘化丙啶(Annexin V-FITC/PI)流式细胞仪检测细胞的凋亡率；Western Blot法检测细胞TLR2、TRAF6、TGFβ、VEGF、MMP2、 Survivin和Livin蛋白的表达。
结果：消癌解毒方能改变H22荷瘤小鼠移植瘤多个基因的表达,并能显著影响多个与肿瘤生长、凋亡和免疫相关的信号通路；下调H22荷瘤小鼠MMP9、MMP12、VEGF和TGFβ,上调TIMP2和IRF1基因的表达。消癌解毒方含药血清能明显抑制人肝癌SMMC-7721细胞在体外的增殖,抑制率以24h时效果最佳,分别为低剂量组(4.2%)、中剂量组(12.1%)、高剂量组(35.8%)、顺铂组(35.3%),消癌解毒方高剂量组与顺铂组无统计学差异(P>0.05)；消癌解毒方能明显促进肝癌细胞的凋亡,电镜下SMMC-7721细胞出现明显的细胞凋亡的形态学改变；Annexin V-FITC/PI流式细胞仪检测消癌解毒方含药血清作用人肝癌SMMC-7721细胞24h后的凋亡率,高剂量组(23.04±1.6%)与顺铂组(22.84±4.4%)差异无统计学意义(P>0.05)；Western Blot法检测发现,消癌解毒方各剂量组TLR2、TRAF6、TGFβ、 VEGF、MMP2、Survivin和Livin蛋白的表达明显低于空白对照组。
结论：消癌解毒方能抑制H22荷瘤小鼠移植瘤的生长,影响多个与肿瘤增殖、凋亡和免疫相关的基因和信号通路；下调H22荷瘤小鼠MMP9、MMP12、VEGF和TGFβ基因,上调TIMP2和IRF1基因的表达。消癌解毒方含药血清能抑制人肝癌SMMC-7721细胞的增殖,促进其凋亡；下调TLR2、TRAF6、TGFβ、VEGF、MMP2、Survivin和Livin蛋白的表达。这些可能是消癌解毒方发挥抗癌作用的机制。
Objective:Found out more signaling pathways and cytokines associated with Xiao'ai Jiedu Prescription (XJP) through detection of tumor gene expression profiles of H22tumor-bearing mice and further explore the antitumor mechanism of XJP by cell experiment from the cellular and molecular level.
Methods:In animal experiments, H22tumor-bearing mice were divided into normal control group,low-dosage XJR group,medium-dosage XJR group,high-dosage XJR group,and Cisplatin group.The differences of gene expression of tumor tissues were discovered by using gene chip technology.The antitumor mechanism of signaling pathways and gene expression were found out by using Gene Ontology (GO) and pathway analysis. The expression of MMP9,MMP12,TIMP2,VEGF and TGF-β gene was detected with real-time quantitative PCR (Realtime-PCR).
In cell experiment, human hepatoma SMMC-7721cells were cultured together with pharmacological serum of XJP. The effect of XJP on inhibiting the growth of SMMC-7721was evaluated by methyl thiazolyl tetrazolium (MTT) assay. The morphology of apoptotic cells was observed through electron microscope and the apoptosis rate was detected with Annexin V-FITC by flowcytometry. The expression of TLR2,TRAF6,TGFp, VEGF, MMP2, Survivin and Livin protein was detected with using Western Blot.
Results:XJP could change expression of multiple genes in H22tumor-bearing mice, and also significantly affect multiple signaling pathways of tumor growth, apoptosis and immune. XJP could decrease the expression of MMP9,MMP12,VEGF and TGFβ, but increase the expression of TIMP2and IRF1.
Pharmacological serum of XJP could significantly inhibite the proliferation of human hepatoma SMMC-7721cells with the best efficiency in24hours.The inhibition rates were4.2%(low-dosage XJR group),12.1%(medium-dosage XJR group),35.8%(high-dosage XJR group), and35.3%(Cisplatin group),and the effect of high-dosage XJR group was similar to that of Cisplatin group(P>0.05). Pharmacological serum of XJP can significantly promote the apoptosis of human hepatoma SMMC-7721cells. Cells showed significant apoptosis morphological changes under electron microscopy. The apoptosis rates were detected after pharmacological serum of XJP acting on human hepatoma SMMC-7721cells for24h with Annexin V-FITC by flowcytometry, and the effect of high-dosage XJR group (23.0±1.6%) was similar to that of Cisplatin group (22.8±4.4%)(P>0.05). As for TLR2,TRAF6,TGF-P,VEGF,MMP2,Survivin and Livin protein expressing contents, the groups of XJP were significantly lower than the normal control group.
Conclusion:XJP could inhibit the tumors'growth of H22tumor-bearing mice, and affect tumor proliferation, apoptosis and immune-related genes and signaling pathways.It could decrease the expression of MMP9, MMP12, VEGF and TGF-β of H22tumor-bearing mice, but increase the expression of TIMP2and IRF1. Pharmacological serum of XJP could inhibit the proliferation of human hepatoma SMMC-7721cells and induce the apoptosis.It could reduce the expression of TLR2, TRAF6, TGF-β, VEGF, MMP2and Survivin and Livin protein. All of these may be the anti-tumor mechanism of the XJP.
方法：动物实验部分,H22荷瘤小鼠随机分为空白对照组,消癌解毒方低、中、高剂量组和顺铂组。应用基因芯片技术,检测各组H22荷瘤小鼠肿瘤组织的差异表达基因；应用Gene Ontology (GO)和pathway分析,找出与消癌解毒方抗癌机制相关的信号通路和基因；并用实时定量PCR法(Realtime-PCR)验证MMP9、MMP12、TIMP2、VEGF和TGFβ等基因的表达。细胞实验部分,以低、中、高剂量组的消癌解毒方含药血清培养人肝癌SMMC-7721细胞,噻唑蓝还原法(MTT)检测消癌解毒方对肝癌细胞的抑制作用；电镜观察细胞的凋亡形态；膜联蛋白A5一绿色荧光素/碘化丙啶(Annexin V-FITC/PI)流式细胞仪检测细胞的凋亡率；Western Blot法检测细胞TLR2、TRAF6、TGFβ、VEGF、MMP2、 Survivin和Livin蛋白的表达。
结果：消癌解毒方能改变H22荷瘤小鼠移植瘤多个基因的表达,并能显著影响多个与肿瘤生长、凋亡和免疫相关的信号通路；下调H22荷瘤小鼠MMP9、MMP12、VEGF和TGFβ,上调TIMP2和IRF1基因的表达。消癌解毒方含药血清能明显抑制人肝癌SMMC-7721细胞在体外的增殖,抑制率以24h时效果最佳,分别为低剂量组(4.2%)、中剂量组(12.1%)、高剂量组(35.8%)、顺铂组(35.3%),消癌解毒方高剂量组与顺铂组无统计学差异(P>0.05)；消癌解毒方能明显促进肝癌细胞的凋亡,电镜下SMMC-7721细胞出现明显的细胞凋亡的形态学改变；Annexin V-FITC/PI流式细胞仪检测消癌解毒方含药血清作用人肝癌SMMC-7721细胞24h后的凋亡率,高剂量组(23.04±1.6%)与顺铂组(22.84±4.4%)差异无统计学意义(P>0.05)；Western Blot法检测发现,消癌解毒方各剂量组TLR2、TRAF6、TGFβ、 VEGF、MMP2、Survivin和Livin蛋白的表达明显低于空白对照组。
结论：消癌解毒方能抑制H22荷瘤小鼠移植瘤的生长,影响多个与肿瘤增殖、凋亡和免疫相关的基因和信号通路；下调H22荷瘤小鼠MMP9、MMP12、VEGF和TGFβ基因,上调TIMP2和IRF1基因的表达。消癌解毒方含药血清能抑制人肝癌SMMC-7721细胞的增殖,促进其凋亡；下调TLR2、TRAF6、TGFβ、VEGF、MMP2、Survivin和Livin蛋白的表达。这些可能是消癌解毒方发挥抗癌作用的机制。
Objective:Found out more signaling pathways and cytokines associated with Xiao'ai Jiedu Prescription (XJP) through detection of tumor gene expression profiles of H22tumor-bearing mice and further explore the antitumor mechanism of XJP by cell experiment from the cellular and molecular level.
Methods:In animal experiments, H22tumor-bearing mice were divided into normal control group,low-dosage XJR group,medium-dosage XJR group,high-dosage XJR group,and Cisplatin group.The differences of gene expression of tumor tissues were discovered by using gene chip technology.The antitumor mechanism of signaling pathways and gene expression were found out by using Gene Ontology (GO) and pathway analysis. The expression of MMP9,MMP12,TIMP2,VEGF and TGF-β gene was detected with real-time quantitative PCR (Realtime-PCR).
In cell experiment, human hepatoma SMMC-7721cells were cultured together with pharmacological serum of XJP. The effect of XJP on inhibiting the growth of SMMC-7721was evaluated by methyl thiazolyl tetrazolium (MTT) assay. The morphology of apoptotic cells was observed through electron microscope and the apoptosis rate was detected with Annexin V-FITC by flowcytometry. The expression of TLR2,TRAF6,TGFp, VEGF, MMP2, Survivin and Livin protein was detected with using Western Blot.
Results:XJP could change expression of multiple genes in H22tumor-bearing mice, and also significantly affect multiple signaling pathways of tumor growth, apoptosis and immune. XJP could decrease the expression of MMP9,MMP12,VEGF and TGFβ, but increase the expression of TIMP2and IRF1.
Pharmacological serum of XJP could significantly inhibite the proliferation of human hepatoma SMMC-7721cells with the best efficiency in24hours.The inhibition rates were4.2%(low-dosage XJR group),12.1%(medium-dosage XJR group),35.8%(high-dosage XJR group), and35.3%(Cisplatin group),and the effect of high-dosage XJR group was similar to that of Cisplatin group(P>0.05). Pharmacological serum of XJP can significantly promote the apoptosis of human hepatoma SMMC-7721cells. Cells showed significant apoptosis morphological changes under electron microscopy. The apoptosis rates were detected after pharmacological serum of XJP acting on human hepatoma SMMC-7721cells for24h with Annexin V-FITC by flowcytometry, and the effect of high-dosage XJR group (23.0±1.6%) was similar to that of Cisplatin group (22.8±4.4%)(P>0.05). As for TLR2,TRAF6,TGF-P,VEGF,MMP2,Survivin and Livin protein expressing contents, the groups of XJP were significantly lower than the normal control group.
Conclusion:XJP could inhibit the tumors'growth of H22tumor-bearing mice, and affect tumor proliferation, apoptosis and immune-related genes and signaling pathways.It could decrease the expression of MMP9, MMP12, VEGF and TGF-β of H22tumor-bearing mice, but increase the expression of TIMP2and IRF1. Pharmacological serum of XJP could inhibit the proliferation of human hepatoma SMMC-7721cells and induce the apoptosis.It could reduce the expression of TLR2, TRAF6, TGF-β, VEGF, MMP2and Survivin and Livin protein. All of these may be the anti-tumor mechanism of the XJP.
引文
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