P300/CBP相关因子在肠型胃癌中的表达及功能研究
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摘要
P300/CBP相关因子(P300/CBP associated factor, PCAF)是哺乳动物中第一个被报道的组蛋白乙酰化转移酶,目前研究认为PCAF通过调节组蛋白和非组蛋白水平而与肿瘤的发生、发展相关联。PCAF的发现为GNAT家族,即GCNS相关的N端乙酰化转移酶(GCNS-relatad-acetytransferas, GNAT),在细胞中的正确定位提供了良好的解释,为肿瘤的分子机理研究和预后判断提供了新的思路,有望作为肿瘤预后判断的一个新的标志物。PCAF基因在肿瘤中的研究目前尚是一个新的领域,迄今为止国内外尚无有关于胃癌中PCAF的实验研究报道。鉴于以上原因,本实验拟研究PCAF基因在肠型胃癌中的表达情况,通过胃腺癌细胞株SGC-7901构建能够稳定表达外源基因PCAF的胃癌细胞系,在此基础上,观察PCAF基因转染对胃癌细胞体内体外生长的抑制作用并探讨其可能机理,为胃癌的诊断和治疗提供新的思路和理论依据。
第一部分PCAF在人肠型胃癌组织和胃腺癌细胞系中的表达
目的：研究PCAF在人肠型胃癌组织和胃腺癌细胞系中的表达情况及其与临床病理的相关性,以初步探讨PCAF在人胃癌中表达的生物学意义。
方法：采用Western blot方法检测永生化人胃粘膜上皮细胞株GES-1和人胃癌细胞株SGC-7901,MKN-45,AGS中PCAF的表达。在406例临床病理资料完整的肠型胃癌及对应癌旁正常胃组织标本中,采用免疫组织化学染色法检测PCAF在组织学水平的表达,结合临床病理资料对实验结果统计分析。
结果：
1. Western-blot检测提示胃腺癌细胞株中PCAF蛋白呈低至痕量表达,而永生
化胃粘膜上皮细胞株GES-1中PCAF为高表达；
2.在肠型胃癌组织中,PCAF的表达与胃壁侵犯、肿瘤瘤体大小、TNM分期、p21、pRb(P< 0.001), PCNA相关(P<0.01)；
3. PCAF在肠型胃癌组织中的表达下调与突变型p53密切相关(P<0.01)；
4.单因素分析显示PCAF/wtp53的患者较其他组合类型的患者有更好的临床预后(P<0.0001)；5.多因素分析显示,肿瘤的部位,淋巴结转移,PCAF/p53表型(P<0.0001),胃
壁侵犯(P=0.001)和PCNA(P=0.018)是判断肠型胃癌预后的独立预后因子。
结论：PCAF特异性下调表达于肠型胃癌组织,可能引起胃癌肿瘤细胞中全组蛋白水平的下调和下游基因的转录失活并可能通过影响肿瘤相关的非组蛋白,参与胃癌发生演进的过程。PCAF与突变型p53的联合检测有助于在临床判断肠型胃癌患者的预后。
第二部分pcDNA3.1-PCAF重组载体的构建及转染细胞的生物学效应
目的：应用定向基因克隆技术,构建PCAF基因真核表达载体pcDNA3.1-PCAF,建立并鉴定能稳定表达外源PCAF基因的胃癌细胞系以研究PCAF基因对SGC-7901细胞生物学行为的影响及其可能的机理。
方法：
1.
(1)从美国ATCC哺乳动物基因组获得PCAF克隆(克隆号10435572)；
(2)通过对pBluescriptR酶切分离获得PCAF的cDNA插入全长,并通过定向克隆技术构建PCAF基因真核表达载体pcDNA3.1-PCAF;
(3)对重组体pcDNA3.1-PCAF进行鉴定；
(4)测序结果重组体所含DNA序列与Genebank公布PCAF序列号比对,结果一致。
2.将PCAF基因的真核表达质粒pcDNA3.1-PCAF和空载体pcDNA3.1质粒分别转化细菌、扩增提取纯化后,应用脂质体Lipo2000介导的方法分别转染体外培养的p53突变型胃腺癌细胞系SGC-7901。G418筛选阳性克隆并扩增培养传代。鉴定稳转基因,并同时检测其下游效应分子p21、pRb等的表达。
3.以成功构建的分别能稳定表达外源pcDNA3.1-PCAF、空载体pcDNA3.1的胃癌细胞系和未转染质粒载体的SGC-7901细胞为研究对象,通过MTT比色、软琼脂克隆集落形成等一系列细胞学功能实验及TUNEL染色的形态学观察,探索稳定转染细胞株中PCAF的表达对肿瘤细胞增殖、凋亡的影响。
结果：
1.
(1)应用脂质体将质粒pcDNA3.1顺利导入大肠杆菌DH5α内,且转化效率高。
(2)酶切电泳结果显示pcDNA3.1质粒被EcoRI、Acc65I成功双酶切。
(3) RT-PCR方法扩增的插入片段电泳证实扩增的片段即为目的片段。重组质粒酶切鉴定预期目的条带。
(4)测序结果重组体所含DNA序列与Genebank公布PCAF序列比对,结果一致。
2.重组体pcDNA3.1-PCAF转染细胞株和空载体pcDNA3.1转染细胞株均获得氨苄青霉素抗性。重组体pcDNA3..1-PCAF转染细胞株和空载体pcDNA3.1转染细胞株因携带有Neor扩标签,均检测到Neor的表达,证实转染成功。Western blot显示重组体pcDNA3.1-PCAF转染细胞株中目的基因PCAF在蛋白质水平上表达均较空载体转染细胞株和未转染细胞株显著增强。
3.对转染前后的细胞观察表明,重组体转染组细胞生长减慢,克隆形成率降低,裸鼠体内成瘤受到抑制,但凋亡变化不明显。
结论：
1.应用基因克隆技术成功构建PCAF基因真核表达载体pcDNA3.1-PCAF。
2.成功构建分别能稳定表达外源pcDNA3.1-PCAF、空载体pcDNA-3.1的胃癌细胞系PCAF-7901和Vec-7901。
3.通过软琼脂克隆形成实验和裸鼠成瘤等功能学研究发现,PCAF基因在体内和体外实验中均可表现出显著的抑瘤能力,PCAF还可阻滞胃癌细胞的G1/S期转化,但对凋亡没有观察到明显作用。
PCAF (P300/CBP associated factor), a recently identified protein, also known as the first mammalian histone acetyltransferases which have been found.The present studies demonstrated that PCAF functions as a negative regulator of cell transformation and tumor cell growth through the regulation of histones and other cancer-related non-histones.PCAF might be broadly involved in diverse type of activated signaling pathways and tumorigenesis. The identification of PCAF supplies a new aim for molecular mechanism of tumor. Consequentially, it is a new target gene of much promise for gene therapy, but the study on PCAF gene in cancer just now began.To our knowledge, this is the first report about the expression of PCAF in gastric carcinoma.According to the mentioned above,we performed the following experiments. Firstly,we investigated the expression of PCAF in intestinal type gastric cancer gastric cancer tissue samples and explored its correlation with clinical and pathological characters.Then we established and identified gastric carcinoma cell lines(SGC-7901) transfected by exogenous gene PCAF.Based on above work, we investigated whether the exogenous gene PCAF transfer could inhibit the growth of gastric carcinoma cell lines in vitro and in vivo, and explored the possible machanism of this effect.Purpose a theoretical basis of genic diagnosis and therapy for intestinal-type gastric carcinoma.
Part I Expression of PCAF in intestinal-type gastric carcinoma tissues and gastric adenocarcinoma cell lines.
Objective:To determine the expression of PCAF in gastric cancer and to investigate the association of PCAF with gastric cancer.
Methods:Wesern blot analysis were used to detect the expression level of protein of PCAF in gastric carcinoma cell lines (SGC-7901, MKN-45, AGS) and immortalized gastric mucosa epithelial cell line GES-1. Immunohistochemistry was 1performed to evaluate the expression of PCAF in a large subset containing 406 intestinal type gastric cancer samples. Correlationship between the expression of PCAF and clinical pathological characters was investigated.
Results:
1. Western blot analysis revealed that all gastric cancer cell lines including AGS, MKN-45 and SGC-7901 exhibited significantly lower levels of PCAF expression compared to those in immortalized gastric mucosa epithelial cell line GES-1 (P<0.05).
2. Statistical analysis displayed a significant correlation in PCAF expression with the gastric wall invasion, tumor size, TNM stage, p21, pRb (P<0.001) and PCNA (P<0.01) in intestinal type gastric cancer specimens.
3. A reduced PCAF protein expression correlated significantly with a mutant type p53 protein expression (P<0.01).
4. Univariate analysis indicated that the patients demonstrating the high-PCAF/wild type p53 expression have a significantly (P<0.0001) better overall survival (OS).
5. Multivariate analysis indicated that the location, lymph node metastasis, PCAF/p53 (P<0.0001), gastric wall invasion (P=0.001) and PCNA (P=0.018) are independently significant prognostic factors for OS.
Conclusions:Reduced expression of PCAF plays an important role in the development of intestinal type gastric cancer and correlates with a poor clinical outcome. PCAF/p53 phenotype may be an independent bio-marker for prognosis in gastric carcinoma
Part II Biological effect of recombinant vector in stably transfected gastric cacinoma cell lines PCAF-7901
Objective:To construct a eukaryotic expression plasmid of PCAF gene:pcDNA3.1-PCAF, in order to study its effect on the biological behavior of gastric carcinoma cell line SGC-7901 in vitro and in vivo.
Methods:
1.
(1) PCAF clone (ATCC Catalog No.10435572) was obtained from the Mammalian Genome Collection.
(2) The full-length PCAF cDNA insert was isolated from pBluescriptR by double digestion of EcoRI and Acc65I, and then subcloned into the mammalian expression vector pcDNA3.1 (-) with the sites of EcoRI and Acc65I. The eukaryotic expression vector of PCAF was constructed by double restriction endonucleases cleavage directional clone method.
(3) Double restriction endonucleases cleavage and sequencing methods were used to identify the eukaryotic expression vector of PCAF gene.
(4) DNA sequencing was performed to confirm the construction.
2.
Two different plasmids including a recombinate pcDNA3.1-PCAF and an empty pcDNA3.1 vector were prepared by transformation of bacterium, amplification and purification of plasmids.Then two kinds of plasmids were reseparately transferred into gastric carcinoma cell line SGC-7901 cultured in vitro by using lipofectamine 2000. After transfection, positive clones were screened with G418 and expanded by culture.The expression of the Neo'tag-gene was detected by RT-PCR to confirm whether the combinant vector DNA integrated with the genomic DNA of SGC-7901. Western blot methods were used to analysis expression of PCAF protein in SGC-7901 cells before and after transfection.
3.
MTT growth test, flow cytometry analysis were used in vitro to study the effects of PCAF expression on transfected cells proliferation. Tumor growth in nude mice was used to access the tumorigenicity of gastric cancer cells. Apoptosis cells were detected by TUNEL staining.
Results:
1.
(1) Vector pcDNA3.1 was introduced into coli DH5a with Lipo 2000.
(2) Vector pcDNA3.1 can be successful cleavage by double restriction endonucleases EcoRl and Acc65I.
(3) Double restriction endonucleases cleavage identification indicated the expected straps.
(4) DNA sequencing was performed to confirm the construction.
2.
All of the two cell lines transfected by cooresponding plasmid acquired resistance to neomycin. The Neo'-tag gene was detected by RT-PCR in cell lines un-transfected due to lack of Neo'-tag. Western-blot showed that the PCAF were expressed higher in cell lines transfected by pcDNA3.1-PCAF than in cell lines un-transfected and transfected by an empty vector on protein level.
3.
Transfected with PCAF eukaryotic expression vector could significantly inhibit growth compared with the untransfected cells in the MTT assay. Flow cytometry analysis showed the proportion of G0/G1 phase cells in PCAF-7901 group was significantly higher than the proportion in the control group. The apoptotic indexes among PCAF-7901, Vec-7901 and SGC-7901 were determined by TUNEL. There was no obvious difference among the three groups.
Conclusions:
1. The eukaryotic expression vector of PCAF gene was successfully constructed by techniques of gene engineering.
2. The eukaryotic vector was transfected successfully to SGC-7901 cells with liposome2000, which integrated with SGC-7901 cell genome and markedly enhanced the expression of PCAF protein in SGC-7901 cells.
3. PCAF was able to suppress tumorigenicity of gastric cancer cells both in vitro and in vivo, including colony formation in soft agar and tumor formation in nude mice. PCAF could also inhibit intestinal type gastric cancer cells entering S phase from G1 phase. PCAF cannot induce apoptosis
第一部分PCAF在人肠型胃癌组织和胃腺癌细胞系中的表达
目的：研究PCAF在人肠型胃癌组织和胃腺癌细胞系中的表达情况及其与临床病理的相关性,以初步探讨PCAF在人胃癌中表达的生物学意义。
方法：采用Western blot方法检测永生化人胃粘膜上皮细胞株GES-1和人胃癌细胞株SGC-7901,MKN-45,AGS中PCAF的表达。在406例临床病理资料完整的肠型胃癌及对应癌旁正常胃组织标本中,采用免疫组织化学染色法检测PCAF在组织学水平的表达,结合临床病理资料对实验结果统计分析。
结果：
1. Western-blot检测提示胃腺癌细胞株中PCAF蛋白呈低至痕量表达,而永生
化胃粘膜上皮细胞株GES-1中PCAF为高表达；
2.在肠型胃癌组织中,PCAF的表达与胃壁侵犯、肿瘤瘤体大小、TNM分期、p21、pRb(P< 0.001), PCNA相关(P<0.01)；
3. PCAF在肠型胃癌组织中的表达下调与突变型p53密切相关(P<0.01)；
4.单因素分析显示PCAF/wtp53的患者较其他组合类型的患者有更好的临床预后(P<0.0001)；5.多因素分析显示,肿瘤的部位,淋巴结转移,PCAF/p53表型(P<0.0001),胃
壁侵犯(P=0.001)和PCNA(P=0.018)是判断肠型胃癌预后的独立预后因子。
结论：PCAF特异性下调表达于肠型胃癌组织,可能引起胃癌肿瘤细胞中全组蛋白水平的下调和下游基因的转录失活并可能通过影响肿瘤相关的非组蛋白,参与胃癌发生演进的过程。PCAF与突变型p53的联合检测有助于在临床判断肠型胃癌患者的预后。
第二部分pcDNA3.1-PCAF重组载体的构建及转染细胞的生物学效应
目的：应用定向基因克隆技术,构建PCAF基因真核表达载体pcDNA3.1-PCAF,建立并鉴定能稳定表达外源PCAF基因的胃癌细胞系以研究PCAF基因对SGC-7901细胞生物学行为的影响及其可能的机理。
方法：
1.
(1)从美国ATCC哺乳动物基因组获得PCAF克隆(克隆号10435572)；
(2)通过对pBluescriptR酶切分离获得PCAF的cDNA插入全长,并通过定向克隆技术构建PCAF基因真核表达载体pcDNA3.1-PCAF;
(3)对重组体pcDNA3.1-PCAF进行鉴定；
(4)测序结果重组体所含DNA序列与Genebank公布PCAF序列号比对,结果一致。
2.将PCAF基因的真核表达质粒pcDNA3.1-PCAF和空载体pcDNA3.1质粒分别转化细菌、扩增提取纯化后,应用脂质体Lipo2000介导的方法分别转染体外培养的p53突变型胃腺癌细胞系SGC-7901。G418筛选阳性克隆并扩增培养传代。鉴定稳转基因,并同时检测其下游效应分子p21、pRb等的表达。
3.以成功构建的分别能稳定表达外源pcDNA3.1-PCAF、空载体pcDNA3.1的胃癌细胞系和未转染质粒载体的SGC-7901细胞为研究对象,通过MTT比色、软琼脂克隆集落形成等一系列细胞学功能实验及TUNEL染色的形态学观察,探索稳定转染细胞株中PCAF的表达对肿瘤细胞增殖、凋亡的影响。
结果：
1.
(1)应用脂质体将质粒pcDNA3.1顺利导入大肠杆菌DH5α内,且转化效率高。
(2)酶切电泳结果显示pcDNA3.1质粒被EcoRI、Acc65I成功双酶切。
(3) RT-PCR方法扩增的插入片段电泳证实扩增的片段即为目的片段。重组质粒酶切鉴定预期目的条带。
(4)测序结果重组体所含DNA序列与Genebank公布PCAF序列比对,结果一致。
2.重组体pcDNA3.1-PCAF转染细胞株和空载体pcDNA3.1转染细胞株均获得氨苄青霉素抗性。重组体pcDNA3..1-PCAF转染细胞株和空载体pcDNA3.1转染细胞株因携带有Neor扩标签,均检测到Neor的表达,证实转染成功。Western blot显示重组体pcDNA3.1-PCAF转染细胞株中目的基因PCAF在蛋白质水平上表达均较空载体转染细胞株和未转染细胞株显著增强。
3.对转染前后的细胞观察表明,重组体转染组细胞生长减慢,克隆形成率降低,裸鼠体内成瘤受到抑制,但凋亡变化不明显。
结论：
1.应用基因克隆技术成功构建PCAF基因真核表达载体pcDNA3.1-PCAF。
2.成功构建分别能稳定表达外源pcDNA3.1-PCAF、空载体pcDNA-3.1的胃癌细胞系PCAF-7901和Vec-7901。
3.通过软琼脂克隆形成实验和裸鼠成瘤等功能学研究发现,PCAF基因在体内和体外实验中均可表现出显著的抑瘤能力,PCAF还可阻滞胃癌细胞的G1/S期转化,但对凋亡没有观察到明显作用。
PCAF (P300/CBP associated factor), a recently identified protein, also known as the first mammalian histone acetyltransferases which have been found.The present studies demonstrated that PCAF functions as a negative regulator of cell transformation and tumor cell growth through the regulation of histones and other cancer-related non-histones.PCAF might be broadly involved in diverse type of activated signaling pathways and tumorigenesis. The identification of PCAF supplies a new aim for molecular mechanism of tumor. Consequentially, it is a new target gene of much promise for gene therapy, but the study on PCAF gene in cancer just now began.To our knowledge, this is the first report about the expression of PCAF in gastric carcinoma.According to the mentioned above,we performed the following experiments. Firstly,we investigated the expression of PCAF in intestinal type gastric cancer gastric cancer tissue samples and explored its correlation with clinical and pathological characters.Then we established and identified gastric carcinoma cell lines(SGC-7901) transfected by exogenous gene PCAF.Based on above work, we investigated whether the exogenous gene PCAF transfer could inhibit the growth of gastric carcinoma cell lines in vitro and in vivo, and explored the possible machanism of this effect.Purpose a theoretical basis of genic diagnosis and therapy for intestinal-type gastric carcinoma.
Part I Expression of PCAF in intestinal-type gastric carcinoma tissues and gastric adenocarcinoma cell lines.
Objective:To determine the expression of PCAF in gastric cancer and to investigate the association of PCAF with gastric cancer.
Methods:Wesern blot analysis were used to detect the expression level of protein of PCAF in gastric carcinoma cell lines (SGC-7901, MKN-45, AGS) and immortalized gastric mucosa epithelial cell line GES-1. Immunohistochemistry was 1performed to evaluate the expression of PCAF in a large subset containing 406 intestinal type gastric cancer samples. Correlationship between the expression of PCAF and clinical pathological characters was investigated.
Results:
1. Western blot analysis revealed that all gastric cancer cell lines including AGS, MKN-45 and SGC-7901 exhibited significantly lower levels of PCAF expression compared to those in immortalized gastric mucosa epithelial cell line GES-1 (P<0.05).
2. Statistical analysis displayed a significant correlation in PCAF expression with the gastric wall invasion, tumor size, TNM stage, p21, pRb (P<0.001) and PCNA (P<0.01) in intestinal type gastric cancer specimens.
3. A reduced PCAF protein expression correlated significantly with a mutant type p53 protein expression (P<0.01).
4. Univariate analysis indicated that the patients demonstrating the high-PCAF/wild type p53 expression have a significantly (P<0.0001) better overall survival (OS).
5. Multivariate analysis indicated that the location, lymph node metastasis, PCAF/p53 (P<0.0001), gastric wall invasion (P=0.001) and PCNA (P=0.018) are independently significant prognostic factors for OS.
Conclusions:Reduced expression of PCAF plays an important role in the development of intestinal type gastric cancer and correlates with a poor clinical outcome. PCAF/p53 phenotype may be an independent bio-marker for prognosis in gastric carcinoma
Part II Biological effect of recombinant vector in stably transfected gastric cacinoma cell lines PCAF-7901
Objective:To construct a eukaryotic expression plasmid of PCAF gene:pcDNA3.1-PCAF, in order to study its effect on the biological behavior of gastric carcinoma cell line SGC-7901 in vitro and in vivo.
Methods:
1.
(1) PCAF clone (ATCC Catalog No.10435572) was obtained from the Mammalian Genome Collection.
(2) The full-length PCAF cDNA insert was isolated from pBluescriptR by double digestion of EcoRI and Acc65I, and then subcloned into the mammalian expression vector pcDNA3.1 (-) with the sites of EcoRI and Acc65I. The eukaryotic expression vector of PCAF was constructed by double restriction endonucleases cleavage directional clone method.
(3) Double restriction endonucleases cleavage and sequencing methods were used to identify the eukaryotic expression vector of PCAF gene.
(4) DNA sequencing was performed to confirm the construction.
2.
Two different plasmids including a recombinate pcDNA3.1-PCAF and an empty pcDNA3.1 vector were prepared by transformation of bacterium, amplification and purification of plasmids.Then two kinds of plasmids were reseparately transferred into gastric carcinoma cell line SGC-7901 cultured in vitro by using lipofectamine 2000. After transfection, positive clones were screened with G418 and expanded by culture.The expression of the Neo'tag-gene was detected by RT-PCR to confirm whether the combinant vector DNA integrated with the genomic DNA of SGC-7901. Western blot methods were used to analysis expression of PCAF protein in SGC-7901 cells before and after transfection.
3.
MTT growth test, flow cytometry analysis were used in vitro to study the effects of PCAF expression on transfected cells proliferation. Tumor growth in nude mice was used to access the tumorigenicity of gastric cancer cells. Apoptosis cells were detected by TUNEL staining.
Results:
1.
(1) Vector pcDNA3.1 was introduced into coli DH5a with Lipo 2000.
(2) Vector pcDNA3.1 can be successful cleavage by double restriction endonucleases EcoRl and Acc65I.
(3) Double restriction endonucleases cleavage identification indicated the expected straps.
(4) DNA sequencing was performed to confirm the construction.
2.
All of the two cell lines transfected by cooresponding plasmid acquired resistance to neomycin. The Neo'-tag gene was detected by RT-PCR in cell lines un-transfected due to lack of Neo'-tag. Western-blot showed that the PCAF were expressed higher in cell lines transfected by pcDNA3.1-PCAF than in cell lines un-transfected and transfected by an empty vector on protein level.
3.
Transfected with PCAF eukaryotic expression vector could significantly inhibit growth compared with the untransfected cells in the MTT assay. Flow cytometry analysis showed the proportion of G0/G1 phase cells in PCAF-7901 group was significantly higher than the proportion in the control group. The apoptotic indexes among PCAF-7901, Vec-7901 and SGC-7901 were determined by TUNEL. There was no obvious difference among the three groups.
Conclusions:
1. The eukaryotic expression vector of PCAF gene was successfully constructed by techniques of gene engineering.
2. The eukaryotic vector was transfected successfully to SGC-7901 cells with liposome2000, which integrated with SGC-7901 cell genome and markedly enhanced the expression of PCAF protein in SGC-7901 cells.
3. PCAF was able to suppress tumorigenicity of gastric cancer cells both in vitro and in vivo, including colony formation in soft agar and tumor formation in nude mice. PCAF could also inhibit intestinal type gastric cancer cells entering S phase from G1 phase. PCAF cannot induce apoptosis
引文
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