重组人生长激素对人胃癌裸鼠移植瘤及骨髓的影响
摘要
目的探讨重组人生长激素(rhGH)在体内对人胃癌细胞生长的影响和部分机制以及对骨髓造血功能的影响。
方法本课题通过对人胃癌细胞株(MKN45)进行细胞培养,成功建立人胃癌细胞裸鼠移植瘤模型。实验分为对照组、顺铂(DDP)组、重组人生长激素(rhGH)组和DDP+rhGH组,每组分给药结束后次日和第3日2个时间点,每组每点6组裸鼠。连续给药6天:rhGH皮下注射、DDP腹腔注射、对照组给予同体积生理盐水。分别于给药结束后次日和第3日应用流式细胞仪、免疫组化、原位末端标记(TUNEL)法、逆转录聚合酶链反应(RT-PCR)、酶联免疫(ELISA)、骨髓涂片和骨髓病理学等技术对下述指标进行检测:给药后瘤体体积及肿瘤抑制率、裸鼠体重、脏器系数、移植瘤细胞周期、细胞增殖指数(PI)、DNA抑制率、核增殖抗原(PCNA)、凋亡指数(AI)、血清生长激素(GH)、胰岛素样生长因子-Ⅰ(IGF-Ⅰ)、胰岛素样生长因子结合蛋白(IGFBP)-3、血管内皮生长因子(VEGF)、移植瘤IGF-ⅠmRNA、IGF-ⅠRmRNA、IGFBP-3mRNA和VEGFmRNA的表达、骨髓细胞计数、骨髓病理形态学。
结果①瘤体体积、肿瘤抑制率、裸鼠体重、脏器系数:给药结束后第1、3天,DDP组、DDP+rhGH组与对照组、rhGH组比较,瘤体生长明显缓慢,肿瘤抑制率明显升高,裸鼠体重明显减轻,脾脏系数明显降低(p＜0.05);而DDP组与DDP+rhGH组、对照组与rhGH组比较瘤体体积、肿瘤抑制率、裸鼠体重、脏器系数均无统计学意义(p＞0.05)。②细胞周期:给药结束后第1、3天胃癌移植瘤DDP组、DDP+rhGH组S期细胞比对照组、rhGH组明显减少(p＜0.05);但各组G_0-G_1期和G_2-M期细胞比较均无统计学意义;而且rhGH组与对照组、DDP+rhGH组与DDP组各期细胞比较无差异(p＞0.05)。③PI和DNA抑制率:给药结束后第1、3天各组胃癌移植瘤细胞PI均无统计学意义(p＞0.05);但DDP组、DDP+rhGH组DNA抑制率较对照组、rhGH组升高。④PCNA和AI:给药结束后第1天DDP组胃癌移植瘤PCNA比对照组、rhGH组降低,而DDP组、DDP+rhGH组AI比对照组、rhGH组升高(p＜0.05);给药结束后第3天DDP组、DDP+rhGH组PCNA比对照组、rhGH组降低(p＜0.05),AI升高(p＜0.05);而rhGH组与对照组、DDP+rhGH组与DDP组PCNA和AI比较均无统计学差异(p＞0.05)。⑤逆转录聚合酶链反应:给药结束后第1、3天rhGH组的IGF-Ⅰ、IGF-ⅠR的mRNA表达量较对照组没有明显增加,IGFBP-3、VEGF的mRNA表达量较对照组明显增加,DDP组、DDP+rhGH组的IGFBP-3 mRNA表达量较对照组、rhGH组明显增加,DDP+rhGH组增加的更明显;给药结束后第3天DDP+rhGH组的VEGF mRNA表达量明显降低。⑥血清学检测:第1天rhGH组、DDP+rhGH组的GH、IGF-Ⅰ、IGFBP-3较对照组、DDP组明显升高(p＜0.05),而DDP组的VEGF较对照组、rhGH组明显降低(p＜0.05);第3天hGH、IGF-Ⅰ、IGFBP-3各组无统计学差异(p＞0.05),而DDP组、DDP+rhGH组的VEGF较对照组、rhGH组明显降低(p＜0.05)。⑦骨髓涂片计数:给药结束后第1、3天荷人胃癌裸鼠DDP组中的粒细胞系较其他三组明显降低(p＜0.05);单核细胞系较其他三组明显升高(p＜0.05);红细胞系较对照组、rhGH组明显降低(p＜0.05);各组间淋巴细胞系无统计学意义;而rhGH组与对照组、DDP+rhGH组与DDP组各细胞系比较无明显差异(p＞0.05)。⑧骨髓病理形态学观察:给药结束后第1天,DDP组中细胞数目减少,多核巨细胞、粒系细胞减少,近成熟粒细胞明显减少,多数细胞核浓缩;其他各组细胞增生活跃,组织结构及各系细胞比例基本正常。给药结束后第3天,DDP组中细胞数目相对减少,组织结构及各系细胞比例基本正常,部分细胞核浓缩;其他各组细胞增生活跃,组织结构及各系细胞比例基本正常。
结论短期应用rhGH不会促进人胃癌细胞的增殖分裂,其机制可能是rhGH短暂升高血清中GH、IGF-Ⅰ,并同时升高IGFBP-3,不会增加人胃癌细胞中IGF-ⅠmRNA、IGF-ⅠR mRNA的表达,同时增加人胃癌细胞中IGFBP-3mRNA的表达;与化疗药合用后明显降低VEGFmRNA。rhGH对化疗后的荷瘤裸鼠骨髓粒细胞系和红细胞系具有保护作用,并能改善骨髓组织结构。
Objective To study effects recombinant human growth hormone on growth of human gastric cancer cell and part mechanism in vivo and on hematopoietic function of bone marrow of nude mice.
Methods In our study,human gastric cancer xenograft model of node mice was successfully founded after human gastric cancer cell line(MKN45)was cultured. Experiment was divided into control group,cisplatin(DDP)group(celiac injection, DDP),recombinant human growth hormone(rhGH)group(subcutanenous injection rhGH)and DDP+rhGH group(celiac injection,DDP and subcutanenous injection, rhGH)and 6 nude mouse in each group.and drugs were used for 6 days.We investigated the effects of rhGH on below index of nude mouse:volume of tumor, inhibitory rate of tumor,weight of nude mouse,coefficient of organ,cell cycle,cell proliferation index(PI),DNA inhibitory rate,apoptosis rate,caryon proliferation antigen(PCNA),apoptosis index(AI)of xenograft,growth hormone(GH),insulin-like growth factor-Ⅰ(IGF-Ⅰ),insulin-like growth factor binding protein(IGFBP)-3, vascular endothelial growth factor(VEGF)of blood serum,IGF-ⅠmRNA, insulin-like growth factor-Ⅰecoptor(IGF-ⅠR)mRNA,IGFBP-3 mRNA and VEGFmRNA of xenograft count of myeloid cells and myeloid pathomorphology by flow cytometry,immuno- histochemistry,Terminal Deoxynucleotidyl Transferase -mediated deoxyuridine triphosphate biotin nick end labeling(TUNEL),Reverse transcriptase-polymerase chain reaction(RT-PCR),Enzyme linked immunosorbent assay(ELISA),bone marrow slides and myeloid pathology on the next day and the third day of completing use of drugs later respectively.
Results①Volume of xenograft,Tumor inhibitory rate,Weight of nude mouse and Organ coefficient:On the next day and the third day of completing use of drugs later, xenograft grew obviously slowly,tumor inhibitory rate obviously rose,weight of nude mouse obviously decreased and organ coefficient of spleen obviously also dropped in DDP group and DDP+rhGH group compared with control group and rhGH group(p＜0.05);but volume of xenograft,tumor inhibitory rate,weight of nude mouse and organ coefficient were not remarkably different between DDP group and DDP+rhGH group or between control group and rhGH group(p＞0.05).②Cycle of cell:Cells of gastric cancer xenograft in S phase distictly diminished in DDP group and DDP+rhGH group compared with control group and rhGH group(p＜0.05)on the next day and the third day of completing use of drugs later;but there was not statistically significant in G_0-G_1 phase and G2-M phase among all groups and it was not statistically significant between DDP group and DDP+rhGH group or between control group and rhGH group yet(p＞0.05).③Proliferation index(PI)and DNA inhibitory rate:On the next day and the third day of completing use of drugs later, there was not statistically significant in PI among all groups(p＞0.05),but DNA inhibitory rate rose in DDP group and DDP+rhGH group compared with control group and rhGH group.④Caryon proliferation antigen(PCNA)and Apoptosis Index (AI):On the next day of completing use of drugs later,PCNA obviously dropped in DDP group compared with control group and rhGH group and AI obviously rose in DDP group and DDP+rhGH group compared with control group and rhGH group(p＜0.05);meanwhile,on the third day of completing use of drugs later,PCNA obviously dropped and AI obviously rose in DDP group and DDP+rhGH group compared with control group and rhGH group(p＜0.05).But PCNA and AI were not statistical difference between DDP group and DDP+rhGH group or between control group and rhGH group(p＞0.05).⑤Examination of RT-PCR:On the next day and the third day of completing use of drugs later,express of IGF-ⅠmRNA and IGF-ⅠR mRNA did not obviously increase,but express of IGFBP-3 mRNA and VEGF mRNA obviously increased in rhGH group compared with control group,meanwhile,express of IGFBP-3 mRNA also obviously increased in DDP group and DDP+rhGH group compared with control group and rhGH group,and it more expressed in DDP+rhGH group.On the third day of completing use of drugs later,express of VEGF mRNA obviously dropped in DDP+rhGH group.⑥Examination of blood serum:On the next day of completing use of drugs later,GH,IGF-Ⅰ,IGFBP-3 of blood serum of nude mouse obviously rose in rhGH group and DDP+rhGH group compared with control group and DDP group,but VEGF obviously dropped in DDP group compared with control group and rhGH group(p＜0.05).On the third day of completing use of drugs later,VEGF obviously dropped in DDP group and DDP+rhGH group compared with control group and rhGH group(p＜0.05)and there was no statistic difference in GH,IGF-Ⅰand IGFBP-3 among all groups.⑦Count of bone marrow slides:On the next day and the third day of completing use of drugs later,granulocytic series of bone marrow obviously dropped and monocytic series obviously rose in DDP group compared with other three groups and erythrocytic series also dropped in DDP group Compared with control group and rhGH group(p＜0.05),but there was no statistic difference in lymphocytic series among all groups and it was so in all cell series between rhGH group and control group or between DDP+rhGH group with DDP group.⑧pathomorphology of bone marrow:On the next day of completing use of drugs later,all cells,multinucleated giant cell,granulocyt and near mature granulocyt decreased and cellular nucleus of most cells concentrated in DDP group.On the third day of completing use of drugs later,all cells decrease relatively and constitution of tissue and ratio of all cell series were normal on the whole and part cellular nucleus of most cells concentrated.But cells actively proliferated and constitution of tissue and ratio of all cell series were normal on the whole in other three groups on the next day and the third day of completing use of drugs later.
Conclusion Our results indicated rhGH in short time use did not improve proliferation of human gastric cancer cell lines.Its mechanism was possibly that rhGH transiently rose GH,IGF-Ⅰand IGFBP-3 of blood serum and did not increase express of IGF-ⅠmRNA and IGF-ⅠR mRNA but increased IGFBP-3 mRNA in human grastic cancer cells,meanwhile,rhGH obviously dropped express of VEGF mRNA combining with chemotherapic drug.RhGH could protect granulocytic series and erythrocytic series of marrow and could improve constitution of tissue of marrow in chemotherapied rats with bearing gastric cancer.
方法本课题通过对人胃癌细胞株(MKN45)进行细胞培养,成功建立人胃癌细胞裸鼠移植瘤模型。实验分为对照组、顺铂(DDP)组、重组人生长激素(rhGH)组和DDP+rhGH组,每组分给药结束后次日和第3日2个时间点,每组每点6组裸鼠。连续给药6天:rhGH皮下注射、DDP腹腔注射、对照组给予同体积生理盐水。分别于给药结束后次日和第3日应用流式细胞仪、免疫组化、原位末端标记(TUNEL)法、逆转录聚合酶链反应(RT-PCR)、酶联免疫(ELISA)、骨髓涂片和骨髓病理学等技术对下述指标进行检测:给药后瘤体体积及肿瘤抑制率、裸鼠体重、脏器系数、移植瘤细胞周期、细胞增殖指数(PI)、DNA抑制率、核增殖抗原(PCNA)、凋亡指数(AI)、血清生长激素(GH)、胰岛素样生长因子-Ⅰ(IGF-Ⅰ)、胰岛素样生长因子结合蛋白(IGFBP)-3、血管内皮生长因子(VEGF)、移植瘤IGF-ⅠmRNA、IGF-ⅠRmRNA、IGFBP-3mRNA和VEGFmRNA的表达、骨髓细胞计数、骨髓病理形态学。
结果①瘤体体积、肿瘤抑制率、裸鼠体重、脏器系数:给药结束后第1、3天,DDP组、DDP+rhGH组与对照组、rhGH组比较,瘤体生长明显缓慢,肿瘤抑制率明显升高,裸鼠体重明显减轻,脾脏系数明显降低(p＜0.05);而DDP组与DDP+rhGH组、对照组与rhGH组比较瘤体体积、肿瘤抑制率、裸鼠体重、脏器系数均无统计学意义(p＞0.05)。②细胞周期:给药结束后第1、3天胃癌移植瘤DDP组、DDP+rhGH组S期细胞比对照组、rhGH组明显减少(p＜0.05);但各组G_0-G_1期和G_2-M期细胞比较均无统计学意义;而且rhGH组与对照组、DDP+rhGH组与DDP组各期细胞比较无差异(p＞0.05)。③PI和DNA抑制率:给药结束后第1、3天各组胃癌移植瘤细胞PI均无统计学意义(p＞0.05);但DDP组、DDP+rhGH组DNA抑制率较对照组、rhGH组升高。④PCNA和AI:给药结束后第1天DDP组胃癌移植瘤PCNA比对照组、rhGH组降低,而DDP组、DDP+rhGH组AI比对照组、rhGH组升高(p＜0.05);给药结束后第3天DDP组、DDP+rhGH组PCNA比对照组、rhGH组降低(p＜0.05),AI升高(p＜0.05);而rhGH组与对照组、DDP+rhGH组与DDP组PCNA和AI比较均无统计学差异(p＞0.05)。⑤逆转录聚合酶链反应:给药结束后第1、3天rhGH组的IGF-Ⅰ、IGF-ⅠR的mRNA表达量较对照组没有明显增加,IGFBP-3、VEGF的mRNA表达量较对照组明显增加,DDP组、DDP+rhGH组的IGFBP-3 mRNA表达量较对照组、rhGH组明显增加,DDP+rhGH组增加的更明显;给药结束后第3天DDP+rhGH组的VEGF mRNA表达量明显降低。⑥血清学检测:第1天rhGH组、DDP+rhGH组的GH、IGF-Ⅰ、IGFBP-3较对照组、DDP组明显升高(p＜0.05),而DDP组的VEGF较对照组、rhGH组明显降低(p＜0.05);第3天hGH、IGF-Ⅰ、IGFBP-3各组无统计学差异(p＞0.05),而DDP组、DDP+rhGH组的VEGF较对照组、rhGH组明显降低(p＜0.05)。⑦骨髓涂片计数:给药结束后第1、3天荷人胃癌裸鼠DDP组中的粒细胞系较其他三组明显降低(p＜0.05);单核细胞系较其他三组明显升高(p＜0.05);红细胞系较对照组、rhGH组明显降低(p＜0.05);各组间淋巴细胞系无统计学意义;而rhGH组与对照组、DDP+rhGH组与DDP组各细胞系比较无明显差异(p＞0.05)。⑧骨髓病理形态学观察:给药结束后第1天,DDP组中细胞数目减少,多核巨细胞、粒系细胞减少,近成熟粒细胞明显减少,多数细胞核浓缩;其他各组细胞增生活跃,组织结构及各系细胞比例基本正常。给药结束后第3天,DDP组中细胞数目相对减少,组织结构及各系细胞比例基本正常,部分细胞核浓缩;其他各组细胞增生活跃,组织结构及各系细胞比例基本正常。
结论短期应用rhGH不会促进人胃癌细胞的增殖分裂,其机制可能是rhGH短暂升高血清中GH、IGF-Ⅰ,并同时升高IGFBP-3,不会增加人胃癌细胞中IGF-ⅠmRNA、IGF-ⅠR mRNA的表达,同时增加人胃癌细胞中IGFBP-3mRNA的表达;与化疗药合用后明显降低VEGFmRNA。rhGH对化疗后的荷瘤裸鼠骨髓粒细胞系和红细胞系具有保护作用,并能改善骨髓组织结构。
Objective To study effects recombinant human growth hormone on growth of human gastric cancer cell and part mechanism in vivo and on hematopoietic function of bone marrow of nude mice.
Methods In our study,human gastric cancer xenograft model of node mice was successfully founded after human gastric cancer cell line(MKN45)was cultured. Experiment was divided into control group,cisplatin(DDP)group(celiac injection, DDP),recombinant human growth hormone(rhGH)group(subcutanenous injection rhGH)and DDP+rhGH group(celiac injection,DDP and subcutanenous injection, rhGH)and 6 nude mouse in each group.and drugs were used for 6 days.We investigated the effects of rhGH on below index of nude mouse:volume of tumor, inhibitory rate of tumor,weight of nude mouse,coefficient of organ,cell cycle,cell proliferation index(PI),DNA inhibitory rate,apoptosis rate,caryon proliferation antigen(PCNA),apoptosis index(AI)of xenograft,growth hormone(GH),insulin-like growth factor-Ⅰ(IGF-Ⅰ),insulin-like growth factor binding protein(IGFBP)-3, vascular endothelial growth factor(VEGF)of blood serum,IGF-ⅠmRNA, insulin-like growth factor-Ⅰecoptor(IGF-ⅠR)mRNA,IGFBP-3 mRNA and VEGFmRNA of xenograft count of myeloid cells and myeloid pathomorphology by flow cytometry,immuno- histochemistry,Terminal Deoxynucleotidyl Transferase -mediated deoxyuridine triphosphate biotin nick end labeling(TUNEL),Reverse transcriptase-polymerase chain reaction(RT-PCR),Enzyme linked immunosorbent assay(ELISA),bone marrow slides and myeloid pathology on the next day and the third day of completing use of drugs later respectively.
Results①Volume of xenograft,Tumor inhibitory rate,Weight of nude mouse and Organ coefficient:On the next day and the third day of completing use of drugs later, xenograft grew obviously slowly,tumor inhibitory rate obviously rose,weight of nude mouse obviously decreased and organ coefficient of spleen obviously also dropped in DDP group and DDP+rhGH group compared with control group and rhGH group(p＜0.05);but volume of xenograft,tumor inhibitory rate,weight of nude mouse and organ coefficient were not remarkably different between DDP group and DDP+rhGH group or between control group and rhGH group(p＞0.05).②Cycle of cell:Cells of gastric cancer xenograft in S phase distictly diminished in DDP group and DDP+rhGH group compared with control group and rhGH group(p＜0.05)on the next day and the third day of completing use of drugs later;but there was not statistically significant in G_0-G_1 phase and G2-M phase among all groups and it was not statistically significant between DDP group and DDP+rhGH group or between control group and rhGH group yet(p＞0.05).③Proliferation index(PI)and DNA inhibitory rate:On the next day and the third day of completing use of drugs later, there was not statistically significant in PI among all groups(p＞0.05),but DNA inhibitory rate rose in DDP group and DDP+rhGH group compared with control group and rhGH group.④Caryon proliferation antigen(PCNA)and Apoptosis Index (AI):On the next day of completing use of drugs later,PCNA obviously dropped in DDP group compared with control group and rhGH group and AI obviously rose in DDP group and DDP+rhGH group compared with control group and rhGH group(p＜0.05);meanwhile,on the third day of completing use of drugs later,PCNA obviously dropped and AI obviously rose in DDP group and DDP+rhGH group compared with control group and rhGH group(p＜0.05).But PCNA and AI were not statistical difference between DDP group and DDP+rhGH group or between control group and rhGH group(p＞0.05).⑤Examination of RT-PCR:On the next day and the third day of completing use of drugs later,express of IGF-ⅠmRNA and IGF-ⅠR mRNA did not obviously increase,but express of IGFBP-3 mRNA and VEGF mRNA obviously increased in rhGH group compared with control group,meanwhile,express of IGFBP-3 mRNA also obviously increased in DDP group and DDP+rhGH group compared with control group and rhGH group,and it more expressed in DDP+rhGH group.On the third day of completing use of drugs later,express of VEGF mRNA obviously dropped in DDP+rhGH group.⑥Examination of blood serum:On the next day of completing use of drugs later,GH,IGF-Ⅰ,IGFBP-3 of blood serum of nude mouse obviously rose in rhGH group and DDP+rhGH group compared with control group and DDP group,but VEGF obviously dropped in DDP group compared with control group and rhGH group(p＜0.05).On the third day of completing use of drugs later,VEGF obviously dropped in DDP group and DDP+rhGH group compared with control group and rhGH group(p＜0.05)and there was no statistic difference in GH,IGF-Ⅰand IGFBP-3 among all groups.⑦Count of bone marrow slides:On the next day and the third day of completing use of drugs later,granulocytic series of bone marrow obviously dropped and monocytic series obviously rose in DDP group compared with other three groups and erythrocytic series also dropped in DDP group Compared with control group and rhGH group(p＜0.05),but there was no statistic difference in lymphocytic series among all groups and it was so in all cell series between rhGH group and control group or between DDP+rhGH group with DDP group.⑧pathomorphology of bone marrow:On the next day of completing use of drugs later,all cells,multinucleated giant cell,granulocyt and near mature granulocyt decreased and cellular nucleus of most cells concentrated in DDP group.On the third day of completing use of drugs later,all cells decrease relatively and constitution of tissue and ratio of all cell series were normal on the whole and part cellular nucleus of most cells concentrated.But cells actively proliferated and constitution of tissue and ratio of all cell series were normal on the whole in other three groups on the next day and the third day of completing use of drugs later.
Conclusion Our results indicated rhGH in short time use did not improve proliferation of human gastric cancer cell lines.Its mechanism was possibly that rhGH transiently rose GH,IGF-Ⅰand IGFBP-3 of blood serum and did not increase express of IGF-ⅠmRNA and IGF-ⅠR mRNA but increased IGFBP-3 mRNA in human grastic cancer cells,meanwhile,rhGH obviously dropped express of VEGF mRNA combining with chemotherapic drug.RhGH could protect granulocytic series and erythrocytic series of marrow and could improve constitution of tissue of marrow in chemotherapied rats with bearing gastric cancer.
引文
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