直肠腺癌发生、发展与转归的凋亡相关分子机制的研究
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摘要
直肠癌是消化系统最常见的恶性肿瘤之一。其死亡率高预后差,大部分直肠癌就诊时为进展期直肠癌。近年来我国直肠癌发病率呈上升化、年轻化趋势。直肠癌的发生、发展和转归与细胞凋亡有密切关系。凋亡调控失常可导致细胞增生失衡,常被认为是肿瘤形成的机制之一。深入开展相关凋亡基因与直肠癌关系的研究有利于我们进一步了解直肠癌发病机理,为探索直肠癌一级预防及有效的基因治疗手段奠定基础。有关直肠癌细胞凋亡的研究逐渐成为基础和临床医学研究的热点,呈现良好的前景。
第一部分:A:直肠腺癌组织凋亡相关基因家族表达谱变化的基因芯片研究
本研究应用基因芯片技术,分析比较直肠腺癌组织与正常直肠黏膜之间基因表达的差异,以期发现肿瘤组织与正常组织中显著差异表达的凋亡相关基因。
目的:研究直肠腺癌发病过程中相关凋亡基因表达谱的变化。方法:自2005年9月-2008年9月,18例直肠腺癌及相应正常直肠组织取自南京医科大学第一附属医院普外科手术切除的直肠癌标本,分别采用Trizol法及Rneasy Kit法提取及纯化总RNA。PCR扩增细胞凋亡相关基因cDNA芯片486条全长基因,Cartesian Pixsys 7500点样仪点样制备凋亡相关基因cDNA芯片(SBC-R-HC-101-10)三张。逆转录合成及纯化cDNA探针配对18例患者的正常组织和癌组织的mRNA,随机均分为3组。将表达谱芯片和混合探针杂交洗液后,Axon扫描仪进行扫描(分辨率Scan resolution为10μm, PMT 100%)、ImaGene 3.0软件读取数据显著lize处理分析,最后ratio值为Cy3/Cy5,即肿瘤组织/正常组织。表达差异基因筛选标准为ratio≥2为显著上调表达基因,0 B:实时荧光定量PCR法检测直肠腺癌组织TNFRSF7、TNFSF7基因表达
目的通过实时荧光定量PCR法检测直肠腺癌组织及癌旁10cm正常组织TNFRSF7、TNFSF7基因表达,以验证凋亡相关基因表达谱芯片检测结果。方法采集9例患者直肠腺癌及癌旁10cm正常组织样本,纳入标准为:病理分级为低分化腺癌、临床分期为Duke’s C期。实时荧光定量PCR法检测直肠腺癌组织TNFRSF7、TNFSF7基因表达。配对t检验,p<0.05为差异有统计显著性。结果直肠腺癌组织中TNFRSF7、TNFSF7及Actin基因起始相对拷贝数均较癌旁10cm正常粘膜组织显著增高(P均小于0.01)。但以Actin基因起始相对拷贝数分别计算TNFRSF7、TNFSF7基因的起始相对拷贝数比值后发现,TNFRSF7起始相对拷贝数比值在直肠腺癌组织与癌旁正常粘膜间无显著差异(t=1.118,p=0.296),而直肠腺癌中TNFSF7起始相对拷贝数比值较癌旁正常粘膜显著增高(t=7.348,p<0.001)。结论TNFRSF7、TNFSF7在直肠癌组织中高表达,可能与直肠腺癌的发生发展及淋巴结转移密切相关;可作为判断肿瘤分期、指导治疗和预后判断的参考指标。
C:原位杂交法检测直肠腺癌组织TNFRSF7、TNFSF7基因mRNA表达
目的:通过荧光原位杂交法检测直肠腺癌组织及癌旁10cm正常组织TNFRSF7、TNFSF7基因表达,以验证凋亡相关基因表达谱芯片检测结果。方法:采集9例患者直肠腺癌及癌旁10cm正常组织样本,纳入标准为:病理分级为低分化腺癌、临床分期为Duke’s C期。原位杂交法检测直肠腺癌组织TNFRSF7、TNFSF7基因表达。将“信号评分”(染色强度评分×染色面积)作为每个样本的原位杂交染色评分。配对t检验,p<0.05为差异有统计显著性。结果::TNFRSF7、TNFSF7生物素标记探针在直肠腺癌细胞中的杂交信号可见于所有直肠腺癌及相应癌旁10cm直肠粘膜上皮,其中细胞质区域杂交信号的强度较胞核区为弱,TNFRSF7杂交信号的强度较TNFSF7为弱。配对t检验分析原位杂交染色检测结果示直肠腺癌组织中TNFRSF7、TNFSF7基因mRNA染色信号(信号评分)均显著强于癌旁10cm正常粘膜组织(p<0.01)。结论:TNFRSF7、TNFSF7mRNA在直肠癌组织中高表达,可能与直肠癌的发生、发展密切相关,可作为判断肿瘤分期指导治疗和预后判断的参考指标。
D:直肠癌组织中TNFRSF7、TNFSF7蛋白的表达及临床意义
探讨直肠癌组织中TNFRSF7、TNFSF7蛋白的表达及其临床意义。采用免疫组化SP法检测60例直肠腺癌组织及癌旁组织中TNFRSF7、TNFSF7蛋白的表达。结果:TNFRSF7、TNFSF7在直肠癌组织中的阳性表达率分别为1.67%、33.33%;在直肠癌旁组织中均不表达。经统计学分析:TNFSF7在直肠癌组织和直肠癌旁组织中存在显著差异(p<0.05)。结论TNFSF7与直肠癌的发生发展密切相关,可作为判断肿瘤分期、指导治疗和预后判断的参考指标。
第二部分:A:直肠癌中TNFSF7的表达及其对淋巴细胞增殖抑制作用的研究
探讨TNFSF7基因在直肠癌中的表达及其在直肠癌免疫逃逸中的作用。逆转录-聚合酶链反应(RT-PCR)法检测TNFSF7在直肠癌细胞系和直肠癌组织的表达;构建TNFSF7真核表达载体,瞬时转染LOVO细胞,与Jurkat细胞共培养,通过细胞增殖试验(CCK8)检测对其淋巴细胞增殖的抑制作用。结果:①直肠癌细胞系SW117和SW620中TNFSF7表达呈阳性, LOVO细胞中TNFSF7表达呈阴性;20例直肠癌组织中6例TNFSF7表达呈阳性,4例癌旁组织TNFSF7表达均呈阴性;②成功构建TNFSF7的真核表达载体,瞬时转染LOVO细胞,与活化的Jurkat细胞共培养。转染TNFSF7后的LOVO与Jurkat共培,Jurkat增殖抑制率(64. 99 %)与空细胞对照组和空载体对照组(37. 98 %、29.96%)相比显著升高(p< 0. 01)。结论:TNFSF7基因在直肠癌中部分呈阳性表达,并可抑制淋巴细胞的增殖活性,在直肠癌细胞免疫逃逸中起了重要作用,可作为指导治疗和预后判断的参考指标。
B:TNFSF7基因沉默对人直肠腺癌细胞株生物学特性的影响
目的:探讨TNFSF7基因沉默对人大肠癌免疫逃逸的影响。方法::根据TNFSF7基因特点,设计合成针对TNFSF7的小干扰RNA(siRNA),并通过脂质体介导小干扰RNA分别转染人肠癌细胞株SW117和SW620,采用RT-PCR检测转染后TNFSF7mRNA表达水平,与Jurkat细胞共培养,CCK-8方法观察TNFSF7表达阳性的人肠癌细胞株TNFSF7基因被沉默后对Jurkat细胞增殖的影响。结果:转染TNFSF7siRNA后明显降低了SW117和SW620细胞株中TNFSF7mRNA的表达,与对照组相比差异有统计学意义, p<0.05。在TNFSF7表达阳性的人肠癌细胞株中沉默TNFSF7后对Jurkat细胞增殖的抑制率明显下降,与对照组相比差异有统计学意义, p<0.05。结论:针对TNFSF7的siRNA能够有效抑制人肠癌细胞株SW117和SW620中TNFSF7基因的表达,沉默组细胞对Jurkat细胞增殖的抑制率明显下降。TNFSF7基因在人肠癌中的阳性表达,可抑制淋巴细胞的增殖活性,在人肠癌细胞免疫逃逸中起了重要作用,并可作为指导治疗和预后判断的参考指标。
Rectal cancer is one of the most common tumors in digestive system.Rectal cancer is a disease of high mortality and poor prognosis.Most of these patients are in an advanced stage when they come to hospital and the exprerience a relapse and metastasis soon after operation. The cancer incidence is rising and younger trend in China. The occurrence of rectal cancer, development and prognosis are closely related with cell apoptosis. Improper regulation of apoptosis can lead to abnormal cell proliferation, which is often regarded as one of the mechanisms of tumor formation. The identification of the relationship between cell apoptosis related genes and the risk of rectal cancer deeply will not only contribute to the understanding of the function of the molecules involved in rectal carcinogenesis but also offer novel molecular tools to diagnosis and reveal potential targets for therapeutic intervention. Apoptosis in the cancer research has become a hot basic and clinical research, which has shown good prospects in clinic.
In this study, we compared the gene expression differences between the rectal adenocarcinoma and normal rectal mucosal with Gene chip technology to find significantly different expression of apoptosis-related genes between tumor tissue and normal tissue.
First part:
A: Study on gene expression profiles related to apoptosis of rectal adenocarcinoma using cDNA Microarray in normal rectal mucosa and rectal adenocarcinoma tissues
Aims: To investigate the gene expression profiles of apoptosis related to rectal cancer.Methods:Between January 1995 and May 2006 , 18 samples of rectal adenocarcinoma and corresponding normal rectum tissue were harvested during the resection for rectal caner in our department. TRIzol and Rneasy Kit were used to extract and purify the total RNA. Polymerase chain reaction (PCR) was employed to amplify 458 apoptosis-related genes in cDNA microarray. Three chips of apoptosis-related gene cDNA microarray (SBC-R-HC-101-10) were prepared by PixSys 7500 DNA Microarray System. We extracted mRNA from both the rectal adenocarcinoma and corresponding normal rectum tissue and produced probes for hybridization wih the cDNA microarray. The 18 samples were divided into three groups in randomization. After the hybridization between cDNA microarray and mixed-probe, Axon scanner (Scan resolution as a resolution of 10μm, PMT 100%) was used to observe the result, and data was analyzed by ImaGene 3.0. Results: Of the 458 apoptosis-related genes, 38 genes were detected having≥2-fold difference of expression between the cancerous and paracancerous tissue, with 27 genes up-regulated and 11 genes down-regulated. Conclusions: The 27genes involved in the whole apotosis pathway might be relevant to the pathogenesis of gastric adenocarcinoma, and further studies are warranted.
B:The mehtod of Real-time fluorescence quantitative PCR was performed to detect the expression of TNFRSF7,TNFRSF7 mRNA in the cancerous and paracancerous tissue.
Aims: To verify the apoptosis-related gene chip test results in former study, we analyzed the expression of TNFRSF7,TNFSF7 mRNA in the cancerous and paracancerous tissue by Real-time fluorescence quantitative PCR.Methods: The cancerous and paracancerous tissue were collectted from 9 patients with rectal cancer. The mehtod of Real-time fluorescence quantitative PCR was performed to detect the expression of TNFRSF7、TNFRSF7 mRNA in the cancerous and paracancerous tissue.Results: The relative gene copy number of TNFRSF7、TNFSF7 and Actin mRNA in cancerous tissue was significant higher than that of paracancerous tissue(p≤0.01). There was no significant difference in the initial relative gene copy number of TNFRSF7 mRNA between cancerous and paracancerous tissue, when we calculate the ratio of the initial relative gene copy number of TNFRSF7、TNFSF7 mRNA according to that of Actin mRNA.Conclusions: The TNFRSF7 and TNFRSF7 play a key role in the oncogenesis development and lymph node metastases of rectal cancer and their expressions could be as useful indexes to assess the malignant level of rectal carcinoma and its clinical prognosis.
C:The method of in situ hybridization was performed to detect the expression of TNFRSF7,TNFSF7 mRNA in the cancerous and paracancerous tissue.
Aims: To verify the apoptosis-related gene chip test results in former study, we analyzed the expression of TNFRSF7,TNFSF7 mRNA in the cancerous and paracancerous tissue by Fluorescence in situ hybridization FISH. Methods:The cancerous and paracancerous tissue were collectted from 9 patients with rectal cancer. The method of in situ hybridization was performed to detect the expression of TNFRSF7,TNFSF7 mRNA in the cancerous and paracancerous tissue. Results: the hybridization signal of biotinylated probe of TNFRSF7 and TNFSF7 could be detected in all kinds of rectal adenocarcinoma and epithelium mucosae of 10cm length adjacent to the tumor, in which the hybridization signal of TNFRSF7 is inferior to that of TNFSF7. The analysis of hybridization results by means of paired t-test demostrated that the signal of mRNA of TNFSF7 and TNFRSF7 was much higher than that of the normal epithelium mucosae 10cm adjacent to the tumor(p<0.01).Conlusions: The TNFRSF7 and TNFRSF7 play a key role in the oncogenesis,development and lymph node metastases of rectal cancer and their expression could be as useful indexes to assess the malignant level of rectal carcinoma and its clinical prognosis.
D:Expression of CD27(TNFRSF7)、CD70(TNFSF7)in rectal cancer tissue and their clinical significance
Aims:To explore the expression of TNFRSF7 and TNFSF in rectal cancer tissue and its clinical significance. Methods: The TNFRSF7 and TNFSF were detected with immunohistochemical stain method in 60 rectal cancer tissues and adjacent non-tumor normal tissues, the relationship between TNFRSF7 and TNFSF and some clinicopathological factors were analyzed withχ2. Results: The positive TNFRSF7 was mostly located in plasmo-cells with rates of 1.67%. While TNFSF7 was mostly located in plasmo-cells with rates of 33.33%. TNFRSF7 expression had no correlation with rectal cancer tissues and adjacent non-tumor normal tissues. The expressions of TNFSF7in rectal carcinoma was significantly higher than that in adjacent non-tumor normal rectal tissues (p<0.05). Conclusions: The gene products TNFSF7 play a key role in the generation and development of rectal cancer and their expression could be as a useful index to assess the malignant level of rectal carcinoma and its clinical prognosis. Second part:
A:Expression of CD70 in rectal carcinoma and its suppressive impact on the proliferation of lymphocytes
Aims:To investigate the expression of the CD70 gene in rectal carcinoma and its role in the immune escape of rectal carcinoma. Methods:The expression of CD70 was determined by RT-PCR. The eukaryotic expression vector was constructed and transiently transfected into the LOVO cell line. After being co-cultured with Jurkat cells, the effects of CD70 on inhibiting lymphocyte proliferation were assessed by the Cell counting kit8(CCK8) . Results:CD70 gene presented in SW117 and SW620 but not in LOVO. CD70 was positive in three cases of rectal carcinoma while it was negative in two cases of rectal tissues adjacent to cancer tissues. The eukaryotic expression vector was successfully constructed and transiently transfected into the LOVO cell line. The LOVO cell line transfected with the CD70 gene can significantly inhibit the proliferation of PHA-activated Jurkat cells.The prolife ration inhibition rate of Jurkat cells cocultured with LOVO cells transfected by the CD70 gene was 64.99%, which was significantly higher than that of Jurkat cells and Jurka cells coculturedwith LOVO cells (37.98% and 29.96%). Conclusions:The CD70 gene is expressed in rectal carcinoma andcan inhibit the proliferation of lymphocytes. The CD70 gene may play an important role in the immune escape of rectal cells and their expression could be useful indexes to assess the malignant level of rectal carcinoma and its clinical prognosis.
B:Silencing of CD70 in rectal carcinoma and its suppressive impact on the proliferation of lymphocytes
Aims: To investigate the feasibility of Silencing of CD70 gene with interfering RNA , and observe the role in the immuneescape of rectal carcinoma.Methods: CD70 specific siRNA oligonucleotides were designed and synthesized artificially. siRNA was transfected into rectal carcinoma SW117 and SW620 cells to inhibit the expression of CD70 in vitro. The mRNA level of CD70 was detected by RT-PCR. After being co-cultured with Jurkat cells, the effects of CD70 on lymphocyte proliferation were assessed by the CCK-8. Results: The expression of CD70 mRNA in siRNA transfected samples was downregulated greatly. There was a significant difference between the RNAi cells and negative controls (P<0.05). The proliferation inhibition rate of Jurkat cells co-cultured with CD70 Silencing cells was significantly lower than the negative controls ( P< 0.05) . Conclusions: The specific siRNA targeting CD70 can effectively the expression of CD70 mRNA, which induce the proliferation inhibition rate of Jurkat cells co-cultured with silencing groups decreased obviously, in human rectal carcinoma SW117 and SW620 cells. The CD70 gene may play an important role in the immune escape of human rectal carcinoma cells and their expression could be useful indexes to assess the malignant level of rectal carcinoma and its clinical prognosis.
第一部分:A:直肠腺癌组织凋亡相关基因家族表达谱变化的基因芯片研究
本研究应用基因芯片技术,分析比较直肠腺癌组织与正常直肠黏膜之间基因表达的差异,以期发现肿瘤组织与正常组织中显著差异表达的凋亡相关基因。
目的:研究直肠腺癌发病过程中相关凋亡基因表达谱的变化。方法:自2005年9月-2008年9月,18例直肠腺癌及相应正常直肠组织取自南京医科大学第一附属医院普外科手术切除的直肠癌标本,分别采用Trizol法及Rneasy Kit法提取及纯化总RNA。PCR扩增细胞凋亡相关基因cDNA芯片486条全长基因,Cartesian Pixsys 7500点样仪点样制备凋亡相关基因cDNA芯片(SBC-R-HC-101-10)三张。逆转录合成及纯化cDNA探针配对18例患者的正常组织和癌组织的mRNA,随机均分为3组。将表达谱芯片和混合探针杂交洗液后,Axon扫描仪进行扫描(分辨率Scan resolution为10μm, PMT 100%)、ImaGene 3.0软件读取数据显著lize处理分析,最后ratio值为Cy3/Cy5,即肿瘤组织/正常组织。表达差异基因筛选标准为ratio≥2为显著上调表达基因,0
目的通过实时荧光定量PCR法检测直肠腺癌组织及癌旁10cm正常组织TNFRSF7、TNFSF7基因表达,以验证凋亡相关基因表达谱芯片检测结果。方法采集9例患者直肠腺癌及癌旁10cm正常组织样本,纳入标准为:病理分级为低分化腺癌、临床分期为Duke’s C期。实时荧光定量PCR法检测直肠腺癌组织TNFRSF7、TNFSF7基因表达。配对t检验,p<0.05为差异有统计显著性。结果直肠腺癌组织中TNFRSF7、TNFSF7及Actin基因起始相对拷贝数均较癌旁10cm正常粘膜组织显著增高(P均小于0.01)。但以Actin基因起始相对拷贝数分别计算TNFRSF7、TNFSF7基因的起始相对拷贝数比值后发现,TNFRSF7起始相对拷贝数比值在直肠腺癌组织与癌旁正常粘膜间无显著差异(t=1.118,p=0.296),而直肠腺癌中TNFSF7起始相对拷贝数比值较癌旁正常粘膜显著增高(t=7.348,p<0.001)。结论TNFRSF7、TNFSF7在直肠癌组织中高表达,可能与直肠腺癌的发生发展及淋巴结转移密切相关;可作为判断肿瘤分期、指导治疗和预后判断的参考指标。
C:原位杂交法检测直肠腺癌组织TNFRSF7、TNFSF7基因mRNA表达
目的:通过荧光原位杂交法检测直肠腺癌组织及癌旁10cm正常组织TNFRSF7、TNFSF7基因表达,以验证凋亡相关基因表达谱芯片检测结果。方法:采集9例患者直肠腺癌及癌旁10cm正常组织样本,纳入标准为:病理分级为低分化腺癌、临床分期为Duke’s C期。原位杂交法检测直肠腺癌组织TNFRSF7、TNFSF7基因表达。将“信号评分”(染色强度评分×染色面积)作为每个样本的原位杂交染色评分。配对t检验,p<0.05为差异有统计显著性。结果::TNFRSF7、TNFSF7生物素标记探针在直肠腺癌细胞中的杂交信号可见于所有直肠腺癌及相应癌旁10cm直肠粘膜上皮,其中细胞质区域杂交信号的强度较胞核区为弱,TNFRSF7杂交信号的强度较TNFSF7为弱。配对t检验分析原位杂交染色检测结果示直肠腺癌组织中TNFRSF7、TNFSF7基因mRNA染色信号(信号评分)均显著强于癌旁10cm正常粘膜组织(p<0.01)。结论:TNFRSF7、TNFSF7mRNA在直肠癌组织中高表达,可能与直肠癌的发生、发展密切相关,可作为判断肿瘤分期指导治疗和预后判断的参考指标。
D:直肠癌组织中TNFRSF7、TNFSF7蛋白的表达及临床意义
探讨直肠癌组织中TNFRSF7、TNFSF7蛋白的表达及其临床意义。采用免疫组化SP法检测60例直肠腺癌组织及癌旁组织中TNFRSF7、TNFSF7蛋白的表达。结果:TNFRSF7、TNFSF7在直肠癌组织中的阳性表达率分别为1.67%、33.33%;在直肠癌旁组织中均不表达。经统计学分析:TNFSF7在直肠癌组织和直肠癌旁组织中存在显著差异(p<0.05)。结论TNFSF7与直肠癌的发生发展密切相关,可作为判断肿瘤分期、指导治疗和预后判断的参考指标。
第二部分:A:直肠癌中TNFSF7的表达及其对淋巴细胞增殖抑制作用的研究
探讨TNFSF7基因在直肠癌中的表达及其在直肠癌免疫逃逸中的作用。逆转录-聚合酶链反应(RT-PCR)法检测TNFSF7在直肠癌细胞系和直肠癌组织的表达;构建TNFSF7真核表达载体,瞬时转染LOVO细胞,与Jurkat细胞共培养,通过细胞增殖试验(CCK8)检测对其淋巴细胞增殖的抑制作用。结果:①直肠癌细胞系SW117和SW620中TNFSF7表达呈阳性, LOVO细胞中TNFSF7表达呈阴性;20例直肠癌组织中6例TNFSF7表达呈阳性,4例癌旁组织TNFSF7表达均呈阴性;②成功构建TNFSF7的真核表达载体,瞬时转染LOVO细胞,与活化的Jurkat细胞共培养。转染TNFSF7后的LOVO与Jurkat共培,Jurkat增殖抑制率(64. 99 %)与空细胞对照组和空载体对照组(37. 98 %、29.96%)相比显著升高(p< 0. 01)。结论:TNFSF7基因在直肠癌中部分呈阳性表达,并可抑制淋巴细胞的增殖活性,在直肠癌细胞免疫逃逸中起了重要作用,可作为指导治疗和预后判断的参考指标。
B:TNFSF7基因沉默对人直肠腺癌细胞株生物学特性的影响
目的:探讨TNFSF7基因沉默对人大肠癌免疫逃逸的影响。方法::根据TNFSF7基因特点,设计合成针对TNFSF7的小干扰RNA(siRNA),并通过脂质体介导小干扰RNA分别转染人肠癌细胞株SW117和SW620,采用RT-PCR检测转染后TNFSF7mRNA表达水平,与Jurkat细胞共培养,CCK-8方法观察TNFSF7表达阳性的人肠癌细胞株TNFSF7基因被沉默后对Jurkat细胞增殖的影响。结果:转染TNFSF7siRNA后明显降低了SW117和SW620细胞株中TNFSF7mRNA的表达,与对照组相比差异有统计学意义, p<0.05。在TNFSF7表达阳性的人肠癌细胞株中沉默TNFSF7后对Jurkat细胞增殖的抑制率明显下降,与对照组相比差异有统计学意义, p<0.05。结论:针对TNFSF7的siRNA能够有效抑制人肠癌细胞株SW117和SW620中TNFSF7基因的表达,沉默组细胞对Jurkat细胞增殖的抑制率明显下降。TNFSF7基因在人肠癌中的阳性表达,可抑制淋巴细胞的增殖活性,在人肠癌细胞免疫逃逸中起了重要作用,并可作为指导治疗和预后判断的参考指标。
Rectal cancer is one of the most common tumors in digestive system.Rectal cancer is a disease of high mortality and poor prognosis.Most of these patients are in an advanced stage when they come to hospital and the exprerience a relapse and metastasis soon after operation. The cancer incidence is rising and younger trend in China. The occurrence of rectal cancer, development and prognosis are closely related with cell apoptosis. Improper regulation of apoptosis can lead to abnormal cell proliferation, which is often regarded as one of the mechanisms of tumor formation. The identification of the relationship between cell apoptosis related genes and the risk of rectal cancer deeply will not only contribute to the understanding of the function of the molecules involved in rectal carcinogenesis but also offer novel molecular tools to diagnosis and reveal potential targets for therapeutic intervention. Apoptosis in the cancer research has become a hot basic and clinical research, which has shown good prospects in clinic.
In this study, we compared the gene expression differences between the rectal adenocarcinoma and normal rectal mucosal with Gene chip technology to find significantly different expression of apoptosis-related genes between tumor tissue and normal tissue.
First part:
A: Study on gene expression profiles related to apoptosis of rectal adenocarcinoma using cDNA Microarray in normal rectal mucosa and rectal adenocarcinoma tissues
Aims: To investigate the gene expression profiles of apoptosis related to rectal cancer.Methods:Between January 1995 and May 2006 , 18 samples of rectal adenocarcinoma and corresponding normal rectum tissue were harvested during the resection for rectal caner in our department. TRIzol and Rneasy Kit were used to extract and purify the total RNA. Polymerase chain reaction (PCR) was employed to amplify 458 apoptosis-related genes in cDNA microarray. Three chips of apoptosis-related gene cDNA microarray (SBC-R-HC-101-10) were prepared by PixSys 7500 DNA Microarray System. We extracted mRNA from both the rectal adenocarcinoma and corresponding normal rectum tissue and produced probes for hybridization wih the cDNA microarray. The 18 samples were divided into three groups in randomization. After the hybridization between cDNA microarray and mixed-probe, Axon scanner (Scan resolution as a resolution of 10μm, PMT 100%) was used to observe the result, and data was analyzed by ImaGene 3.0. Results: Of the 458 apoptosis-related genes, 38 genes were detected having≥2-fold difference of expression between the cancerous and paracancerous tissue, with 27 genes up-regulated and 11 genes down-regulated. Conclusions: The 27genes involved in the whole apotosis pathway might be relevant to the pathogenesis of gastric adenocarcinoma, and further studies are warranted.
B:The mehtod of Real-time fluorescence quantitative PCR was performed to detect the expression of TNFRSF7,TNFRSF7 mRNA in the cancerous and paracancerous tissue.
Aims: To verify the apoptosis-related gene chip test results in former study, we analyzed the expression of TNFRSF7,TNFSF7 mRNA in the cancerous and paracancerous tissue by Real-time fluorescence quantitative PCR.Methods: The cancerous and paracancerous tissue were collectted from 9 patients with rectal cancer. The mehtod of Real-time fluorescence quantitative PCR was performed to detect the expression of TNFRSF7、TNFRSF7 mRNA in the cancerous and paracancerous tissue.Results: The relative gene copy number of TNFRSF7、TNFSF7 and Actin mRNA in cancerous tissue was significant higher than that of paracancerous tissue(p≤0.01). There was no significant difference in the initial relative gene copy number of TNFRSF7 mRNA between cancerous and paracancerous tissue, when we calculate the ratio of the initial relative gene copy number of TNFRSF7、TNFSF7 mRNA according to that of Actin mRNA.Conclusions: The TNFRSF7 and TNFRSF7 play a key role in the oncogenesis development and lymph node metastases of rectal cancer and their expressions could be as useful indexes to assess the malignant level of rectal carcinoma and its clinical prognosis.
C:The method of in situ hybridization was performed to detect the expression of TNFRSF7,TNFSF7 mRNA in the cancerous and paracancerous tissue.
Aims: To verify the apoptosis-related gene chip test results in former study, we analyzed the expression of TNFRSF7,TNFSF7 mRNA in the cancerous and paracancerous tissue by Fluorescence in situ hybridization FISH. Methods:The cancerous and paracancerous tissue were collectted from 9 patients with rectal cancer. The method of in situ hybridization was performed to detect the expression of TNFRSF7,TNFSF7 mRNA in the cancerous and paracancerous tissue. Results: the hybridization signal of biotinylated probe of TNFRSF7 and TNFSF7 could be detected in all kinds of rectal adenocarcinoma and epithelium mucosae of 10cm length adjacent to the tumor, in which the hybridization signal of TNFRSF7 is inferior to that of TNFSF7. The analysis of hybridization results by means of paired t-test demostrated that the signal of mRNA of TNFSF7 and TNFRSF7 was much higher than that of the normal epithelium mucosae 10cm adjacent to the tumor(p<0.01).Conlusions: The TNFRSF7 and TNFRSF7 play a key role in the oncogenesis,development and lymph node metastases of rectal cancer and their expression could be as useful indexes to assess the malignant level of rectal carcinoma and its clinical prognosis.
D:Expression of CD27(TNFRSF7)、CD70(TNFSF7)in rectal cancer tissue and their clinical significance
Aims:To explore the expression of TNFRSF7 and TNFSF in rectal cancer tissue and its clinical significance. Methods: The TNFRSF7 and TNFSF were detected with immunohistochemical stain method in 60 rectal cancer tissues and adjacent non-tumor normal tissues, the relationship between TNFRSF7 and TNFSF and some clinicopathological factors were analyzed withχ2. Results: The positive TNFRSF7 was mostly located in plasmo-cells with rates of 1.67%. While TNFSF7 was mostly located in plasmo-cells with rates of 33.33%. TNFRSF7 expression had no correlation with rectal cancer tissues and adjacent non-tumor normal tissues. The expressions of TNFSF7in rectal carcinoma was significantly higher than that in adjacent non-tumor normal rectal tissues (p<0.05). Conclusions: The gene products TNFSF7 play a key role in the generation and development of rectal cancer and their expression could be as a useful index to assess the malignant level of rectal carcinoma and its clinical prognosis. Second part:
A:Expression of CD70 in rectal carcinoma and its suppressive impact on the proliferation of lymphocytes
Aims:To investigate the expression of the CD70 gene in rectal carcinoma and its role in the immune escape of rectal carcinoma. Methods:The expression of CD70 was determined by RT-PCR. The eukaryotic expression vector was constructed and transiently transfected into the LOVO cell line. After being co-cultured with Jurkat cells, the effects of CD70 on inhibiting lymphocyte proliferation were assessed by the Cell counting kit8(CCK8) . Results:CD70 gene presented in SW117 and SW620 but not in LOVO. CD70 was positive in three cases of rectal carcinoma while it was negative in two cases of rectal tissues adjacent to cancer tissues. The eukaryotic expression vector was successfully constructed and transiently transfected into the LOVO cell line. The LOVO cell line transfected with the CD70 gene can significantly inhibit the proliferation of PHA-activated Jurkat cells.The prolife ration inhibition rate of Jurkat cells cocultured with LOVO cells transfected by the CD70 gene was 64.99%, which was significantly higher than that of Jurkat cells and Jurka cells coculturedwith LOVO cells (37.98% and 29.96%). Conclusions:The CD70 gene is expressed in rectal carcinoma andcan inhibit the proliferation of lymphocytes. The CD70 gene may play an important role in the immune escape of rectal cells and their expression could be useful indexes to assess the malignant level of rectal carcinoma and its clinical prognosis.
B:Silencing of CD70 in rectal carcinoma and its suppressive impact on the proliferation of lymphocytes
Aims: To investigate the feasibility of Silencing of CD70 gene with interfering RNA , and observe the role in the immuneescape of rectal carcinoma.Methods: CD70 specific siRNA oligonucleotides were designed and synthesized artificially. siRNA was transfected into rectal carcinoma SW117 and SW620 cells to inhibit the expression of CD70 in vitro. The mRNA level of CD70 was detected by RT-PCR. After being co-cultured with Jurkat cells, the effects of CD70 on lymphocyte proliferation were assessed by the CCK-8. Results: The expression of CD70 mRNA in siRNA transfected samples was downregulated greatly. There was a significant difference between the RNAi cells and negative controls (P<0.05). The proliferation inhibition rate of Jurkat cells co-cultured with CD70 Silencing cells was significantly lower than the negative controls ( P< 0.05) . Conclusions: The specific siRNA targeting CD70 can effectively the expression of CD70 mRNA, which induce the proliferation inhibition rate of Jurkat cells co-cultured with silencing groups decreased obviously, in human rectal carcinoma SW117 and SW620 cells. The CD70 gene may play an important role in the immune escape of human rectal carcinoma cells and their expression could be useful indexes to assess the malignant level of rectal carcinoma and its clinical prognosis.
引文
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