环氧合酶-2对胃癌淋巴管生成和淋巴转移关系的实验研究
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摘要
胃癌在世界范围内是消化道肿瘤中最常见的恶性肿瘤之一,早期诊断率比较低,目前限于疾病本身及现有的技术条件,外科手术尚不能完全清除胃癌周围区域所有的淋巴结,中晚期胃癌的主要治疗手段为化疗和放疗,化疗药物和放疗在杀灭肿瘤细胞的同时,对正常的组织细胞也产生较大损伤,化疗药物和放疗对肿瘤细胞的疗效低、毒付作用大,寻找新的治疗手段是当务之急。
研究显示,在多数胃癌组织及细胞系中环氧合酶-2(Cyclooxygenase-2, COX-2)表达均异常增高,它可以促进胃癌淋巴侵袭转移及血管的形成,并且与胃癌患者的低生存率密切相关,而选择性抑制COX-2的活性抑制剂可以抑制胃癌相关的血管和淋巴管生成。胃癌组织中COX-2过度表达,COX-2表达与淋巴结转移和肿瘤进展期呈现相关性,同时癌组织中COX-2的高度表达与胃壁中淋巴管的浸润和区域性淋巴结的转移明显相关。近年来有学者提出应用COX-2表达水平评估胃癌的淋巴转移及预后。
前期研究表明胃癌组织中COX-2、VEGF-C、受体VEGFR-3的表达及微淋巴管密度密切相关；本实验采用逆转录聚合酶链式反应检测人胃癌细胞SGC-7901分别加入不同浓度的COX-2抑制剂尼美舒利与加入外源性前列腺素E2(PGE2)后VEGF-C mRNA及蛋白的变化；通过脂质体介导方法,将构建好含有COX-2的重组质粒转染入人胃癌细胞株SGC-7901细胞中,新霉素筛选得到稳定转染胃癌细胞系,采用RT-PCR和Western blot方法分别从mRNA和蛋白质水平检测抑制效果；构建靶向环氧合酶-2表达质粒和在BALB/c裸鼠皮下建立SGC-7901人胃癌细胞动物模型,用环氧合酶-2表达质粒基因转染治疗,环氧合酶-2基因治疗可抑制裸鼠皮下肿瘤的生长和淋巴管的生成。
The gastrointestinal tract tumor is very common in our country.It is very difficult to diagnose it in early stage.Chemotherapy and radiotherapy are the main therapies in late stage.The tumor cell can be killed by these drugs, but meanwhile the normal tissue cell also killed by these drugs.This means all the drugs have a lot of side effect,and their efficacy is very low.So it is urge to find new therapy to cure the gastrointestinal tract tumor. COX-2 frequently detected over-expressed in gastric carcinoma tissues and cell lines, was believed to play a crucial role in promotion of proliferation and angiogenesis in gastric carcinoma. Up-regulation of COX-2 might facilitate invasion of gastric carcinoma and was significantly related to the low survival rate of gastric carcinoma patients. Reduced COX-2 activity could result in decreased angiogenesis, increased apoptosis and suppressed synthesis of prostaglandins.COX-2 was closed related to gastric carcinogenesis and progression with lymph angiogenesis, however the underlying mechanisms are not fully understood.
In gastric carcinoma, the expression rate COX-2 was high, COX-2 expression was positively correlated with clinical stage, and lymph node metastasis; COX-2 play an important role in the carcinogenesis and metastasis of gastric carcinoma, It is that COX-2 in gastric cancer tissues will be of significance.
Objective:
To study the effect of cyclooxygenase-2(COX-2) in gastric cancer and the correlation with lymph angiogenesis and prognosis.
To explore the effect of cyclooxygenase-2(COX-2) gene transfection on the expression level of COX-2 in human gastric carcinoma SGC-7901 cell.
To evaluate the effects of cyclooxygenase-2(COX-2)on tumour growth and lymph angiogenesis in nude mice models.
Methods:
1. The expressions of VEGF-C mRNA and protein were detected by reverse transcription-polymerase chain reaction (RT-PCR) and Western blot in SGC-7901 cell lines by the treatment of selective COX-2 inhibitor Nimesulide at different doses. The expressions of VEGF-C protein were evaluated in SGC-7901 cells treated by PGE2 respectively.
2. The constructed COX-2 gene eukaryotic expression vector was transfected into the human gastric carcinoma SGC-7901 cell by using lipofectamine transfection reagents. and the positive cell clones were obtained through G418 selection after transfection.The expressions of COX-2 mRNA and protein were detected by RT-PCR and Western blot respectively. COX-2 expression plasmid pGenesil-1-COX-2,was constructed and transfected into SGC-7901 cells.Human gastric carcinoma cells of the line SGC-7901 and human umbilical vein COX-2 cells of the line were cultured and stimulatd by the supernatant of the SGC-7901 cells transfected with pGenesil-i-COX-2,MTT method was used to detect the poliferation of the cells.
3. BALB/c mice were inoclated of pGenesil-1, pGenesil-1-COX-2.Other mice were used as untreated control group.Two weeks later mice from each group were killed with the tumours taken out.exprssion of COX-2, vascular endothelial growth factor-C (VEGF-C)and and microlymphatic density (MLD).
Results:
1. Nimesulide could down-regulate the expressions of VEGF-C and protein in a does-dependent manner, the expressions of VEGF-C protein up-regulated by PGE-2 treatment.
2.Following the transfection of the COX-2 recombination plasmid, RNA interference efficently and stably suppressed the COX-2 expression in SGC-7901 cells,and downregulation of COX-2 resulted in significantly inhibition of tumor cell growth in vitro.the growth inhibitory rates were significantly higher in specific COX-2 siRNA group than those in the control.
3.Following the transfection of the COX-2 recombination plasmid,RNA interference efficently and stably suppressed the COX-2 expression in SGC-7901 cells,and downregulation of COX-2,VEGF-C,MLD resulted in significantly inhibition of tumor cell growth.the growth inhibitory rates were significantly higher in specific COX-2 siRNA group than those in the control.
Conclusion:
1. COX-2 over-expression can up-regulate the expression of VEGF-C. VEGF-C might promote lymph node metastasis by a lymphangiogenic pathway, than affect the prognosis of the patients with gastric cancer.
2. Nimesulide could down-regulate the expressions of VEGF-C and protein in a does-dependent manner, the expressions of VEGF-C protein up-regulated by PGE-2 treatment.
3. With the transfection of COX-2 gene vector by using liposome,the expression levels of COX-2 mRNA and protein is significant inhibition of tumor growth in gastric carcinoma SGC-7901 cell.
4. Construction of eukaryotic expression vector expressing the specific shRNA targeting on COX-2 can supress tumour growth and with lymph angiogenesis, COX-2 gene therapy synergizes to suppress gastric carcinoma.
研究显示,在多数胃癌组织及细胞系中环氧合酶-2(Cyclooxygenase-2, COX-2)表达均异常增高,它可以促进胃癌淋巴侵袭转移及血管的形成,并且与胃癌患者的低生存率密切相关,而选择性抑制COX-2的活性抑制剂可以抑制胃癌相关的血管和淋巴管生成。胃癌组织中COX-2过度表达,COX-2表达与淋巴结转移和肿瘤进展期呈现相关性,同时癌组织中COX-2的高度表达与胃壁中淋巴管的浸润和区域性淋巴结的转移明显相关。近年来有学者提出应用COX-2表达水平评估胃癌的淋巴转移及预后。
前期研究表明胃癌组织中COX-2、VEGF-C、受体VEGFR-3的表达及微淋巴管密度密切相关；本实验采用逆转录聚合酶链式反应检测人胃癌细胞SGC-7901分别加入不同浓度的COX-2抑制剂尼美舒利与加入外源性前列腺素E2(PGE2)后VEGF-C mRNA及蛋白的变化；通过脂质体介导方法,将构建好含有COX-2的重组质粒转染入人胃癌细胞株SGC-7901细胞中,新霉素筛选得到稳定转染胃癌细胞系,采用RT-PCR和Western blot方法分别从mRNA和蛋白质水平检测抑制效果；构建靶向环氧合酶-2表达质粒和在BALB/c裸鼠皮下建立SGC-7901人胃癌细胞动物模型,用环氧合酶-2表达质粒基因转染治疗,环氧合酶-2基因治疗可抑制裸鼠皮下肿瘤的生长和淋巴管的生成。
The gastrointestinal tract tumor is very common in our country.It is very difficult to diagnose it in early stage.Chemotherapy and radiotherapy are the main therapies in late stage.The tumor cell can be killed by these drugs, but meanwhile the normal tissue cell also killed by these drugs.This means all the drugs have a lot of side effect,and their efficacy is very low.So it is urge to find new therapy to cure the gastrointestinal tract tumor. COX-2 frequently detected over-expressed in gastric carcinoma tissues and cell lines, was believed to play a crucial role in promotion of proliferation and angiogenesis in gastric carcinoma. Up-regulation of COX-2 might facilitate invasion of gastric carcinoma and was significantly related to the low survival rate of gastric carcinoma patients. Reduced COX-2 activity could result in decreased angiogenesis, increased apoptosis and suppressed synthesis of prostaglandins.COX-2 was closed related to gastric carcinogenesis and progression with lymph angiogenesis, however the underlying mechanisms are not fully understood.
In gastric carcinoma, the expression rate COX-2 was high, COX-2 expression was positively correlated with clinical stage, and lymph node metastasis; COX-2 play an important role in the carcinogenesis and metastasis of gastric carcinoma, It is that COX-2 in gastric cancer tissues will be of significance.
Objective:
To study the effect of cyclooxygenase-2(COX-2) in gastric cancer and the correlation with lymph angiogenesis and prognosis.
To explore the effect of cyclooxygenase-2(COX-2) gene transfection on the expression level of COX-2 in human gastric carcinoma SGC-7901 cell.
To evaluate the effects of cyclooxygenase-2(COX-2)on tumour growth and lymph angiogenesis in nude mice models.
Methods:
1. The expressions of VEGF-C mRNA and protein were detected by reverse transcription-polymerase chain reaction (RT-PCR) and Western blot in SGC-7901 cell lines by the treatment of selective COX-2 inhibitor Nimesulide at different doses. The expressions of VEGF-C protein were evaluated in SGC-7901 cells treated by PGE2 respectively.
2. The constructed COX-2 gene eukaryotic expression vector was transfected into the human gastric carcinoma SGC-7901 cell by using lipofectamine transfection reagents. and the positive cell clones were obtained through G418 selection after transfection.The expressions of COX-2 mRNA and protein were detected by RT-PCR and Western blot respectively. COX-2 expression plasmid pGenesil-1-COX-2,was constructed and transfected into SGC-7901 cells.Human gastric carcinoma cells of the line SGC-7901 and human umbilical vein COX-2 cells of the line were cultured and stimulatd by the supernatant of the SGC-7901 cells transfected with pGenesil-i-COX-2,MTT method was used to detect the poliferation of the cells.
3. BALB/c mice were inoclated of pGenesil-1, pGenesil-1-COX-2.Other mice were used as untreated control group.Two weeks later mice from each group were killed with the tumours taken out.exprssion of COX-2, vascular endothelial growth factor-C (VEGF-C)and and microlymphatic density (MLD).
Results:
1. Nimesulide could down-regulate the expressions of VEGF-C and protein in a does-dependent manner, the expressions of VEGF-C protein up-regulated by PGE-2 treatment.
2.Following the transfection of the COX-2 recombination plasmid, RNA interference efficently and stably suppressed the COX-2 expression in SGC-7901 cells,and downregulation of COX-2 resulted in significantly inhibition of tumor cell growth in vitro.the growth inhibitory rates were significantly higher in specific COX-2 siRNA group than those in the control.
3.Following the transfection of the COX-2 recombination plasmid,RNA interference efficently and stably suppressed the COX-2 expression in SGC-7901 cells,and downregulation of COX-2,VEGF-C,MLD resulted in significantly inhibition of tumor cell growth.the growth inhibitory rates were significantly higher in specific COX-2 siRNA group than those in the control.
Conclusion:
1. COX-2 over-expression can up-regulate the expression of VEGF-C. VEGF-C might promote lymph node metastasis by a lymphangiogenic pathway, than affect the prognosis of the patients with gastric cancer.
2. Nimesulide could down-regulate the expressions of VEGF-C and protein in a does-dependent manner, the expressions of VEGF-C protein up-regulated by PGE-2 treatment.
3. With the transfection of COX-2 gene vector by using liposome,the expression levels of COX-2 mRNA and protein is significant inhibition of tumor growth in gastric carcinoma SGC-7901 cell.
4. Construction of eukaryotic expression vector expressing the specific shRNA targeting on COX-2 can supress tumour growth and with lymph angiogenesis, COX-2 gene therapy synergizes to suppress gastric carcinoma.
引文
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