食管鳞癌血管内皮生长因子C表达和基因沉默干预的临床与实验研究
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摘要
第一部分:食管鳞癌组织中血管内皮生长因子C、D及其受体mRNA的表达及其临床意义
目的研究血管内皮生长因子C(vascular endothelial growth factor-C,VEGF-C)、血管内皮生长因子D (vascular endothelial growth factor-D,VEGF-D)及其受体VEGFR-2 (vascular endothelial growth factor receptor-2)、VEGFR-3 (vascular endothelial growth factor receptor-3) mRNA在食管鳞癌组织中的表达。方法通过实时定量PCR (real-time PCR),检测24例正常食管组织样本和60例食管鳞癌(esophageal squamous cell carcinomas, ESCCs)组织标本中VEGF-C、VEGF-D、VEGFR2和VEGFR3的mRNA表达水平。结果与正常食管组织相比,人ESCC组织中,VEGF-C、VEGF-D、VEGFR2和VEGFR3的mRNA水平分别显著增强3.9倍、1.3倍、2.2倍和8.6倍。结论VEGF-C、VEGF-D及其受体mRNA在食管鳞癌组织中的表达明显高于正常组织,VEGF-C、VEGF-D及其受体mRNA可能与食管鳞癌发生、发展有关。
第二部分:血管内皮生长因子C蛋白表达和食管鳞癌临床病理特征和预后的相关性研究
目的研究VEGF-C在食管鳞癌中的表达,并分析其与临床病理特征、预后的关系。方法运用免疫组织化学法检测73例食管鳞癌组织中VEGF-C蛋白水平表达情况,统计学分析免疫组化细胞染色、临床病理参数和预后的关系。结果食管鳞癌组织中VEGF-C蛋白阳性表达率为53.4%,其蛋白水平的表达与病理分级(P=0.005)、肿瘤浸润深度(depth of tumor invasion, pT)(P=0.021)、淋巴结转移(lymph node metastasis, pN)(P=0.002)和淋巴浸润(P=0.008)有相关性,在对数秩检验的单变量系统分析中,病理分级、pN、分期、淋巴浸润和VEGF-C的P值分别为0.047,0.007,0.018,0.002和0.003 ,表明VEGF-C与上述病理特征存在相关性;多变量系统分析显示,VEGF-C(P=0.0451)和pN(P=0.0029)是影响预后的独立因素。结论VEGF-C蛋白表达与食管鳞癌病理分级、pT、pN和淋巴浸润有关,可能是影响食管鳞癌预后的一个重要指标。
第三部分:血管内皮生长因子C基因过表达和基因沉默载体构建及其对基因表达的影响
目的构建人VEGF-C基因过表达和基因沉默载体,为下一步研究VEGF-C对食管癌增殖的影响奠定基础。方法将包含人VEGF-C编码区的基因片段PCR扩增,插入pEGFP-N1载体,构建VEGF-C基因过表达载体;将抗VEGF-C mRNA形成的短发夹干扰RNA (short hairpin RNA, shRNA),插入pGPU6/GFP/Neo载体,构建VEGF-C基因沉默载体。将两种载体转染人食管癌TE-1细胞株,挑选稳定株,通过real-time PCR技术分析VEGF-C mRNA表达情况,通过免疫荧光染色和酶联免疫吸附试验分析VEGF-C蛋白表达情况。结果设计构建了过表达载体pEGFP-VEGF-C和两个基因沉默载体shRNA-1、shRNA-2,与阴性对照相比,稳定转染VEGF-C过表达载体的TE-1细胞中VEGF-C基因转录、翻译和蛋白分泌显著增强,稳定转染两种shRNA载体的细胞中VEGF-C基因转录、翻译和蛋白分泌水平均显著降低,其中shRNA-2比shRNA-1更能有效地抑制VEGF-C水平。结论VEGF-C过表达载体能增强VEGF-C基因转录、翻译和蛋白分泌,shRNA载体能减弱VEGF-C基因转录、翻译和蛋白分泌。
第四部分:血管内皮生长因子C对食管癌细胞生长增殖影响的实验研究
目的利用稳定转染VEGF-C过表达或基因沉默质粒的TE-1细胞株,分析VEGF-C在对食管癌细胞增殖、转移、癌灶形成和药物敏感性的影响,并建立裸鼠皮下荷瘤模型,分析VEGF-C在裸鼠体内对食管癌生长的影响。方法对于转染VEGF-C过表达和基因沉默质粒的TE-1细胞株,采用CCK-8试剂盒测定其细胞的生长率。各组细胞经顺铂处理后计算增殖率以评估VEGF-C对化学敏感性的影响。采用显微镜计数进行细胞迁移实验和克隆形成率分析,以确定VEGF-C在肿瘤细胞转移中的作用;以定量染色质免疫沉淀反应确定食管癌中VEGF-C的下游效应物CNTN-1。另将生长4周的雄性Balb/C小鼠分别注射稳定转染shRNA-NC、shRNA-2或pEGFP-VEGF-C载体的肿瘤细胞株,每隔三天用游标卡尺测量肿瘤直径,计算肿瘤体积,建立肿瘤生长曲线。结果pEGFP-VEGF-C转染的TE-1细胞增殖率增长1倍,上清液转移细胞增多70%,细胞对顺铂的敏感性未受影响,细胞集落数目增长了1.1倍,CNTN-1转录水平升高;而shRNA-2转染的TE-1细胞生长受到抑制,生长率为对照组的72%,上清液中转移细胞数量减少50%,细胞对顺铂的敏感性未受影响,细胞癌灶增值率低,CNTN-1转录水平降低。动物实验结果显示,在注射转染pEGFP-VEGF-C细胞的裸鼠肿瘤体积显著增长,而注射转染VEGF-C shRNA细胞的裸鼠肿瘤显著减小。结论在体外,VEGF-C过表达可促进食管癌细胞增殖、转移和癌灶形成,VEGF-C基因沉默可抑制食管癌细胞增殖、转移和癌灶形成,CNTN-1可能是食管癌中VEGF-C的下游效应物。基因沉默VEGF-C可明显抑制裸鼠皮下移植瘤生长,以VEGF-C为靶基因的RNA干扰技术可能是一个潜在的治疗人食管癌的方法。
Part one: Gene expression of vascular endothelial growth factor-C and -D and their receptors in esophageal squamous carcinoma tissues
Objective To investigate the gene expression of vascular endothelial growth factor-C (VEGF-C), vascular endothelial growth factor-D (VEGF-D) and their receptors vascular endothelial growth factor receptor-2 (VEGFR-2), vascular endothelial growth factor receptor-3 (VEGFR-3) in esophageal squamous carcinoma. Methods The mRNA levels of VEGF-C, VEGF-D, VEGFR2 and VEGFR3 gene in 24 normal esophageal specimens and 60 esophageal squamous cell carcinomas (ESCCs) were determined by real-time PCR. Results The mRNA levels of VEGF-C, VEGF-D, VEGFR2 and VEGFR3 were significantly upregulated by 3.9-, 1.3-, 2.2- and 8.6-fold, respectively in human ESCC tissues compared with normal esophageal tissues. Conclusions Upregulation of VEGF-C, VEGF-D and their receptors maybe involved in esophageal tumor development and progression.
Part two: Protein expression of vascular endothelial growth factor-C correlates with clinicopathological parameters and a poor prognosis of esophageal squamous cell carcinomas
Objective: To specifically investigate the clinicopathological role of expression of VEGF-C as well as the correlation with clinical outcomes in ESCCs. Methods Seventy-three patients with ESCC resected in our institute were included in this study. Formalin-fixed paraffin-embedded specimens were stained for VEGF-C and the correlation between the staining, its clinicopathological parameters and its prognostic power were analyzed statistically. Results Of the 73 ESCC patients studied, 39 cases (53.4%) were strongly positive for VEGF-C. VEGF-C expression correlated with histological grade (P=0.005), depth of tumor invasion (pT) (P=0.021), lymphnode metastasis (pN) (P=0.002) and lymphatic invasion (P=0.008). In univariate analysis by log-rank test, histological grade, pN, stage, lymphatic invasion and VEGF-C were significant prognostic factors (P=0.047, 0.007, 0.018, 0.002 and 0.003, respectively). In multivariate analysis, high VEGF-C expression (P=0.0451) maintained its independent prognostic influence on overall survival, as well as pN status (P=0.0029). Conclusions Expression of VEGF-C is related to histological grade, pT, pN and lymphatic invasion, and is a prognostic indicator for ESCC.
Part three: Construction of vascular endothelial growth factor-C overexpression and silencing vectors and their interference effects
Objective: Vascular endothelial growth factor-C overexpression and silencing vectors were constructed to provide bases for research on influence of VEGF-C expression on esophageal cancer proliferation. Methods: For VEGF-C overexpression vector, a fragment containing human VEGF-C coding region was amplified by PCR, and then inserted into the pEGFP-N1 vector. For VEGF-C silencing vectors, pGPU6/GFP/Neo vectors containing short hairpin interfering RNA (shRNA) against VEGF-C mRNA were constructed. The human ESCC cell line TE-1 transfected with VEGF-C overexpression and silencing vectors was maintained to generate stable VEGF-C-overexpressing or silencing clones, and VEGF-C mRNA expression was analysed by real time PCR, while protein levels were determined by immunostaining and enzyme-linked immunosorbent assay. Results: The overexpression vector pEGFP-VEGF-C and two silencing vectors (shRNA-1 and shRNA-2) were constructed. VEGF-C transcription, translation and secretion were significantly increased in the VEGF-C-overexpressing TE-1 cells compared with cells transfected with shRNA negative control. Cells transfected both of the shRNA vectors showed reduced VEGF-C transcription, translation and secretion levels. By contrast, shRNA-2 has more potently suppressed VEGF-C level than shRNA-1. Conclusion: The overexpression vector of VEGF-C increased the transcription, translation and secretion of VEGF-C, which were decreased by the silencing vector.
Part four: In vitro effects of vascular endothelial growth factor-C on esophageal cancer proliferation in stably transfected TE-1 cell lines and in vivo effects on esophageal tumor growth in nude mice
Objective: To analysis in vitro effects of vascular endothelial growth factor-C on esophageal cancer proliferation using TE-1 cell lines stably transfected with VEGF-C overexpression or shRNA vectors. And to analysis in vitro effects of vascular endothelial growth factor-C on esophageal cancer tumor growth using nude mice bearing TE-1 cells xenografts as a model. Methods: In vitro growth was measured using CCK-8 kit. To evaluate the effect of VEGF-C on chemosensitivity, the proliferation index was calculated after cisplatin treatment. Migration assay and focus formation assay were conducted under a microscope. Quantitative chromatin immunoprecipitation was carried out to determine the downstream effector of VEGF-C/VEGFR-3 signaling. Male mice at 4 weeks of age were injeted with tumor cells transfected with siRNA-NC, shRNA-2 or pEGFP-VEGF-C vector, respectively. Tumor diameters were measured at regular intervals with digital calipers, the tumor volume was calculated and tumor growth curve was then constructed. Results: pEGFP-VEGF-C transfected TE-1 cells exhibited a 1-fold significant increase in cell proliferation rate, 70 percents increased migrated cells in supernatant, unchanged resistance to cisplatin, 1.1-fold increase colonies numbers and promoted CNTN-1 transcription. In contrast, shRNA-2 transfection inhibited TE-1 cell growth to 72 % of the control, decreased migrated cells in supernatant by 50 percents, did not change resistance to cisplatin, while reduced colonies numbers and CNTN-1 transcripts. A significant increased or decreased tumor size was observed in nude mice injected with pEGFP-VEGF-C-transfected or VEGF-C shRNA-transfected cells, respectively. Conclusion: In vitro, VEGF-C overexpression vector increased cell proliferation, migration and focus formation, which were decreased by VEGF-C silencing vectors. And in vivo, gene silencing could also decreased ploliferation of tumor in nude mice. Besides, CNTN-1 may be the potential downstream effector of VEGF-C.
目的研究血管内皮生长因子C(vascular endothelial growth factor-C,VEGF-C)、血管内皮生长因子D (vascular endothelial growth factor-D,VEGF-D)及其受体VEGFR-2 (vascular endothelial growth factor receptor-2)、VEGFR-3 (vascular endothelial growth factor receptor-3) mRNA在食管鳞癌组织中的表达。方法通过实时定量PCR (real-time PCR),检测24例正常食管组织样本和60例食管鳞癌(esophageal squamous cell carcinomas, ESCCs)组织标本中VEGF-C、VEGF-D、VEGFR2和VEGFR3的mRNA表达水平。结果与正常食管组织相比,人ESCC组织中,VEGF-C、VEGF-D、VEGFR2和VEGFR3的mRNA水平分别显著增强3.9倍、1.3倍、2.2倍和8.6倍。结论VEGF-C、VEGF-D及其受体mRNA在食管鳞癌组织中的表达明显高于正常组织,VEGF-C、VEGF-D及其受体mRNA可能与食管鳞癌发生、发展有关。
第二部分:血管内皮生长因子C蛋白表达和食管鳞癌临床病理特征和预后的相关性研究
目的研究VEGF-C在食管鳞癌中的表达,并分析其与临床病理特征、预后的关系。方法运用免疫组织化学法检测73例食管鳞癌组织中VEGF-C蛋白水平表达情况,统计学分析免疫组化细胞染色、临床病理参数和预后的关系。结果食管鳞癌组织中VEGF-C蛋白阳性表达率为53.4%,其蛋白水平的表达与病理分级(P=0.005)、肿瘤浸润深度(depth of tumor invasion, pT)(P=0.021)、淋巴结转移(lymph node metastasis, pN)(P=0.002)和淋巴浸润(P=0.008)有相关性,在对数秩检验的单变量系统分析中,病理分级、pN、分期、淋巴浸润和VEGF-C的P值分别为0.047,0.007,0.018,0.002和0.003 ,表明VEGF-C与上述病理特征存在相关性;多变量系统分析显示,VEGF-C(P=0.0451)和pN(P=0.0029)是影响预后的独立因素。结论VEGF-C蛋白表达与食管鳞癌病理分级、pT、pN和淋巴浸润有关,可能是影响食管鳞癌预后的一个重要指标。
第三部分:血管内皮生长因子C基因过表达和基因沉默载体构建及其对基因表达的影响
目的构建人VEGF-C基因过表达和基因沉默载体,为下一步研究VEGF-C对食管癌增殖的影响奠定基础。方法将包含人VEGF-C编码区的基因片段PCR扩增,插入pEGFP-N1载体,构建VEGF-C基因过表达载体;将抗VEGF-C mRNA形成的短发夹干扰RNA (short hairpin RNA, shRNA),插入pGPU6/GFP/Neo载体,构建VEGF-C基因沉默载体。将两种载体转染人食管癌TE-1细胞株,挑选稳定株,通过real-time PCR技术分析VEGF-C mRNA表达情况,通过免疫荧光染色和酶联免疫吸附试验分析VEGF-C蛋白表达情况。结果设计构建了过表达载体pEGFP-VEGF-C和两个基因沉默载体shRNA-1、shRNA-2,与阴性对照相比,稳定转染VEGF-C过表达载体的TE-1细胞中VEGF-C基因转录、翻译和蛋白分泌显著增强,稳定转染两种shRNA载体的细胞中VEGF-C基因转录、翻译和蛋白分泌水平均显著降低,其中shRNA-2比shRNA-1更能有效地抑制VEGF-C水平。结论VEGF-C过表达载体能增强VEGF-C基因转录、翻译和蛋白分泌,shRNA载体能减弱VEGF-C基因转录、翻译和蛋白分泌。
第四部分:血管内皮生长因子C对食管癌细胞生长增殖影响的实验研究
目的利用稳定转染VEGF-C过表达或基因沉默质粒的TE-1细胞株,分析VEGF-C在对食管癌细胞增殖、转移、癌灶形成和药物敏感性的影响,并建立裸鼠皮下荷瘤模型,分析VEGF-C在裸鼠体内对食管癌生长的影响。方法对于转染VEGF-C过表达和基因沉默质粒的TE-1细胞株,采用CCK-8试剂盒测定其细胞的生长率。各组细胞经顺铂处理后计算增殖率以评估VEGF-C对化学敏感性的影响。采用显微镜计数进行细胞迁移实验和克隆形成率分析,以确定VEGF-C在肿瘤细胞转移中的作用;以定量染色质免疫沉淀反应确定食管癌中VEGF-C的下游效应物CNTN-1。另将生长4周的雄性Balb/C小鼠分别注射稳定转染shRNA-NC、shRNA-2或pEGFP-VEGF-C载体的肿瘤细胞株,每隔三天用游标卡尺测量肿瘤直径,计算肿瘤体积,建立肿瘤生长曲线。结果pEGFP-VEGF-C转染的TE-1细胞增殖率增长1倍,上清液转移细胞增多70%,细胞对顺铂的敏感性未受影响,细胞集落数目增长了1.1倍,CNTN-1转录水平升高;而shRNA-2转染的TE-1细胞生长受到抑制,生长率为对照组的72%,上清液中转移细胞数量减少50%,细胞对顺铂的敏感性未受影响,细胞癌灶增值率低,CNTN-1转录水平降低。动物实验结果显示,在注射转染pEGFP-VEGF-C细胞的裸鼠肿瘤体积显著增长,而注射转染VEGF-C shRNA细胞的裸鼠肿瘤显著减小。结论在体外,VEGF-C过表达可促进食管癌细胞增殖、转移和癌灶形成,VEGF-C基因沉默可抑制食管癌细胞增殖、转移和癌灶形成,CNTN-1可能是食管癌中VEGF-C的下游效应物。基因沉默VEGF-C可明显抑制裸鼠皮下移植瘤生长,以VEGF-C为靶基因的RNA干扰技术可能是一个潜在的治疗人食管癌的方法。
Part one: Gene expression of vascular endothelial growth factor-C and -D and their receptors in esophageal squamous carcinoma tissues
Objective To investigate the gene expression of vascular endothelial growth factor-C (VEGF-C), vascular endothelial growth factor-D (VEGF-D) and their receptors vascular endothelial growth factor receptor-2 (VEGFR-2), vascular endothelial growth factor receptor-3 (VEGFR-3) in esophageal squamous carcinoma. Methods The mRNA levels of VEGF-C, VEGF-D, VEGFR2 and VEGFR3 gene in 24 normal esophageal specimens and 60 esophageal squamous cell carcinomas (ESCCs) were determined by real-time PCR. Results The mRNA levels of VEGF-C, VEGF-D, VEGFR2 and VEGFR3 were significantly upregulated by 3.9-, 1.3-, 2.2- and 8.6-fold, respectively in human ESCC tissues compared with normal esophageal tissues. Conclusions Upregulation of VEGF-C, VEGF-D and their receptors maybe involved in esophageal tumor development and progression.
Part two: Protein expression of vascular endothelial growth factor-C correlates with clinicopathological parameters and a poor prognosis of esophageal squamous cell carcinomas
Objective: To specifically investigate the clinicopathological role of expression of VEGF-C as well as the correlation with clinical outcomes in ESCCs. Methods Seventy-three patients with ESCC resected in our institute were included in this study. Formalin-fixed paraffin-embedded specimens were stained for VEGF-C and the correlation between the staining, its clinicopathological parameters and its prognostic power were analyzed statistically. Results Of the 73 ESCC patients studied, 39 cases (53.4%) were strongly positive for VEGF-C. VEGF-C expression correlated with histological grade (P=0.005), depth of tumor invasion (pT) (P=0.021), lymphnode metastasis (pN) (P=0.002) and lymphatic invasion (P=0.008). In univariate analysis by log-rank test, histological grade, pN, stage, lymphatic invasion and VEGF-C were significant prognostic factors (P=0.047, 0.007, 0.018, 0.002 and 0.003, respectively). In multivariate analysis, high VEGF-C expression (P=0.0451) maintained its independent prognostic influence on overall survival, as well as pN status (P=0.0029). Conclusions Expression of VEGF-C is related to histological grade, pT, pN and lymphatic invasion, and is a prognostic indicator for ESCC.
Part three: Construction of vascular endothelial growth factor-C overexpression and silencing vectors and their interference effects
Objective: Vascular endothelial growth factor-C overexpression and silencing vectors were constructed to provide bases for research on influence of VEGF-C expression on esophageal cancer proliferation. Methods: For VEGF-C overexpression vector, a fragment containing human VEGF-C coding region was amplified by PCR, and then inserted into the pEGFP-N1 vector. For VEGF-C silencing vectors, pGPU6/GFP/Neo vectors containing short hairpin interfering RNA (shRNA) against VEGF-C mRNA were constructed. The human ESCC cell line TE-1 transfected with VEGF-C overexpression and silencing vectors was maintained to generate stable VEGF-C-overexpressing or silencing clones, and VEGF-C mRNA expression was analysed by real time PCR, while protein levels were determined by immunostaining and enzyme-linked immunosorbent assay. Results: The overexpression vector pEGFP-VEGF-C and two silencing vectors (shRNA-1 and shRNA-2) were constructed. VEGF-C transcription, translation and secretion were significantly increased in the VEGF-C-overexpressing TE-1 cells compared with cells transfected with shRNA negative control. Cells transfected both of the shRNA vectors showed reduced VEGF-C transcription, translation and secretion levels. By contrast, shRNA-2 has more potently suppressed VEGF-C level than shRNA-1. Conclusion: The overexpression vector of VEGF-C increased the transcription, translation and secretion of VEGF-C, which were decreased by the silencing vector.
Part four: In vitro effects of vascular endothelial growth factor-C on esophageal cancer proliferation in stably transfected TE-1 cell lines and in vivo effects on esophageal tumor growth in nude mice
Objective: To analysis in vitro effects of vascular endothelial growth factor-C on esophageal cancer proliferation using TE-1 cell lines stably transfected with VEGF-C overexpression or shRNA vectors. And to analysis in vitro effects of vascular endothelial growth factor-C on esophageal cancer tumor growth using nude mice bearing TE-1 cells xenografts as a model. Methods: In vitro growth was measured using CCK-8 kit. To evaluate the effect of VEGF-C on chemosensitivity, the proliferation index was calculated after cisplatin treatment. Migration assay and focus formation assay were conducted under a microscope. Quantitative chromatin immunoprecipitation was carried out to determine the downstream effector of VEGF-C/VEGFR-3 signaling. Male mice at 4 weeks of age were injeted with tumor cells transfected with siRNA-NC, shRNA-2 or pEGFP-VEGF-C vector, respectively. Tumor diameters were measured at regular intervals with digital calipers, the tumor volume was calculated and tumor growth curve was then constructed. Results: pEGFP-VEGF-C transfected TE-1 cells exhibited a 1-fold significant increase in cell proliferation rate, 70 percents increased migrated cells in supernatant, unchanged resistance to cisplatin, 1.1-fold increase colonies numbers and promoted CNTN-1 transcription. In contrast, shRNA-2 transfection inhibited TE-1 cell growth to 72 % of the control, decreased migrated cells in supernatant by 50 percents, did not change resistance to cisplatin, while reduced colonies numbers and CNTN-1 transcripts. A significant increased or decreased tumor size was observed in nude mice injected with pEGFP-VEGF-C-transfected or VEGF-C shRNA-transfected cells, respectively. Conclusion: In vitro, VEGF-C overexpression vector increased cell proliferation, migration and focus formation, which were decreased by VEGF-C silencing vectors. And in vivo, gene silencing could also decreased ploliferation of tumor in nude mice. Besides, CNTN-1 may be the potential downstream effector of VEGF-C.
引文
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