CagA阳性幽门螺杆菌在促胃癌细胞干性特征增强中的作用及其机制研究
发布时间：2018-07-31 18:24
【摘要】：胃癌是危害人类健康的主要恶性肿瘤之一,全球胃癌的发病率和死亡率居高不下。据最新的统计数据表明,我国胃癌的发病率和死亡率在所有肿瘤中均居第二位,每年死于胃癌的人数高达50万。因此,研究影响胃癌发生发展的因素具有重要意义。目前,世界范围内幽门螺杆菌(Helicobacter pylori,H.pylor)的感染率约50%,部分地区高达80%(Management of Helicobacter pylori infection-the Maastricht IV/Florence Consensus Report,2012)。在我国,H.pylori的感染率总体上也很高,成人中感染率达40-60%(第四次全国幽门螺杆菌感染处理共识报告,2012),WHO早在1994年就已将其列为胃癌的Ⅰ类致癌因子。虽然H.pylori在人群中的感染率很高,但只有部分感染者最终发展为胃癌,究其原因,H.pylori的致病性与其菌株的种类、宿主遗传因素及环境因素等有关。H.pylori菌株类型的不同是导致不同临床结局的重要原因。2012年欧洲马斯特里赫特共识中提到,胃癌的发生发展受H.pylori毒力因子的影响,其循证医学的证据等级为1a。细胞毒素相关基因A(cytotoxin-associated gene A,CagA)编码的CagA蛋白作为重要的毒力因子之一,其阳性菌株感染后导致严重临床后果的危险性明显大于阴性菌株,具有CagA基因的菌株是H.pylori中重要的致病菌株。CagA是由H.pylori的cag致病岛(cag pathogenicity island,cag PAI)上CagA基因编码的蛋白,通过cag PAI编码Ⅳ型分泌系统将CagA“注入”宿主细胞,是H.pylori唯一能进入宿主细胞而发挥生物学作用的蛋白。最新的循证医学证据表明,CagA~+H.pylori菌株增加胃癌发生的风险。CagA转基因小鼠的胃癌发生率明显增加,证实CagA是促进胃癌发生的关键分子。肿瘤干细胞(cancer stem cells,CSCs)学说认为肿瘤组织中存在一小部分具有干细胞性质的细胞群体,具有无限的自我更新和诱导肿瘤发生的能力,是肿瘤产生的种子细胞,由于其同时具有高转移潜能、对放化疗等治疗抵抗等特性,而被认为是恶性肿瘤复发转移的关键。以往有关H.pylori的研究主要集中于其在促进胃癌细胞增殖和抑制胃癌细胞凋亡中的作用。但最新的研究发现,CagA~+H.pylori可以通过诱导胃癌细胞发生上皮-间叶转化(epithelial mesenchymal transition,EMT),从而使胃癌细胞获得胃癌干细胞特征。本课题进一步确认CagA~+h.pylori在促胃癌细胞干性特征增强中的作用,并阐明其机制。因此,本课题丰富了CagA~+h.pylori菌株感染的致病机理,有助于加深CagA~+h.pylori在胃癌发生发展中作用的认识,为特异性根除CagA~+h.pylori提供新的理论依据。【研究目的】1、构建h.pylori感染胃癌细胞模型,评价CagA~+h.pylori对胃癌细胞干性特征的影响;2、探讨CagA~+h.pylori促胃癌细胞干性特征增强的分子机制。【研究方法】1、评价CagA~+h.pylori对胃癌细胞干性特征的影响:(1)构建h.pylori感染胃癌细胞的模型;(2)通过流式细胞技术,分别检测CagA~+h.pylori(h.pylori菌株nctc11637)感染组、caga-h.pylori(以h.pylori菌株nctc11637为背景的caga敲除株)感染组及未感染组中胃癌干细胞表面标志物阳性的胃癌细胞比例;(3)通过pcr从mrna水平进一步分析上述各组中胃癌干细胞表面标志物的转录水平;(4)通过体外成球实验评价上述各组中胃癌细胞的体外成球能力;(5)通过免疫印记(westernblotting,wb)检测上述各组中胃癌细胞干性转录因子的表达水平;(6)光镜下观察上述各组中胃癌细胞形态学的改变,wb检测emt标志物的表达变化。2、探讨CagA~+h.pylori促胃癌细胞干性特征增强的分子机制:(1)通过免疫荧光实验,在激光共聚焦下观察β-catenin在上述各组胃癌细胞中的定位情况;(2)通过双荧光素酶报告基因实验检测上述各组胃癌细胞中wnt/β-catenin信号通路的活化水平;(3)通过wb检测CagA~+h.pylori及caga-h.pylori感染胃癌细胞不同时相点β-catenin核转位关键磷酸化位点ser675和ser552的表达水平;(4)使用c-met抑制剂su11274及pi3k/akt抑制剂gsk690693分别预处理胃癌细胞,通过wb进一步检测CagA~+h.pylori感染后胃癌细胞中β-catenin的ser675和ser552位点磷酸化水平;(5)使用wnt/β-catenin抑制剂xav预处理胃癌细胞,通过流式细胞技术、pcr以及成球实验,分别检测CagA~+h.pylori的感染对胃癌细胞中胃癌干细胞表面标志物阳性的胃癌细胞比例、胃癌干细胞表面标志物mrna水平以及胃癌细胞成球能力的影响;(6)使用wnt/β-catenin抑制剂xav预处理胃癌细胞,通过wb和pcr分别检测CagA~+h.pylori的感染对胃癌细胞中干性转录因子nanog和oct4蛋白表达水平及mrna水平的影响;(7)构建nanog和oct4启动子区域的双荧光素酶报告质粒,通过双荧光素酶报告实验检测CagA~+h.pylori介导的β-catenin核转位对nanog和oct4启动子活性的影响;(8)生物信息学预测β-catenin在nanog和oct4启动子上的可能结合区域,通过染色质免疫共沉淀(chromatinimmunoprecipitation,chip)实验检测β-catenin作用于nanog和oct4启动子的区域;(9)通过c13尿素酶呼气试验及检测血清中caga抗体,将胃癌患者分为CagA~+h.pylori感染组及caga-h.pylori感染组,分别检测两组患者胃癌组织标本中nanog和oct4蛋白表达水平及mrna水平。【研究结果】1、CagA~+h.pylori感染的胃癌细胞,与caga-h.pylori感染组及未感染组相比,更多的胃癌细胞表现出胃癌干细胞样特征;2、CagA~+h.pylori活化wnt/β-catenin信号通路,包括促进β-catenin的核转位及增强β-catenin的转录活性;3、CagA~+h.pylori通过c-met和/或akt介导的通路促β-cateninc末端ser675和ser552位点的磷酸化,使β-catenin发生核转位;4、wnt/β-catenin信号通路的活化是CagA~+h.pylori促胃癌细胞干性特征增强的重要环节;5、wnt/β-catenin信号通路的活化参与CagA~+h.pylori上调干性转录因子nanog和oct4;6、CagA~+h.pylori感染的胃癌患者,与caga-h.pylori感染的胃癌患者相比,胃癌组织标本中nanog和oct4的表达明显增加。【结论】CagA~+h.pylori通过活化wnt/β-catenin信号通路,上调nanog和oct4的表达,促胃癌细胞干性特征增强。【研究意义】目前,国内外指南均推荐高风险人群(慢性萎缩性胃炎、溃疡、肠上皮化生、异型增生及胃癌术后等)根除h.pylori的治疗,但其分子机制并不清楚。本课题证实h.pylori中的高毒力致病菌株——CagA~+h.pylori可以促胃癌细胞干性特征增强,这可能是胃粘膜上皮细胞从异常增生到最终发展为胃癌的重要原因,也可能是胃癌根除术后少数残余胃癌细胞致胃癌复发转移的重要原因。因此,本课题为深入理解和认识H.pylori感染的致病机制提供了新的视角,有助于加深CagA~+H.pylori在胃癌发生发展中作用的认识,为特异性根除CagA~+H.pylori提供新的理论依据。
[Abstract]:Gastric cancer is one of the main malignant tumors that harm human health. The incidence and mortality of global gastric cancer are high. According to the latest statistics, the incidence and mortality of gastric cancer in China are second in all tumors, and the number of people dying of gastric cancer is up to 500 thousand every year. At present, the infection rate of Helicobacter pylori (H.pylor) is about 50% in the world, and in some regions up to 80% (Management of Helicobacter pylori infection-the Maastricht IV/Florence Consensus Report, 2012). In China, the infection rate is also high, and the infection rate in adults is fourth times. The national consensus report on the treatment of Helicobacter pylori infection, 2012), WHO has been listed as a class I carcinogen of gastric cancer as early as 1994. Although the infection rate of H.pylori in the population is very high, only some of the infected people eventually develop into gastric cancer. The cause of the infection is the pathogenicity of H.pylori and the species of its strains, host genetic factors and environmental factors. The difference in the type of.H.pylori isolates is an important cause of different clinical outcomes. The European Maastricht consensus in.2012 is that the occurrence and development of gastric cancer are affected by H.pylori virulence factors, and the evidence level of evidence-based medicine is the CagA protein encoded by the 1a. cytotoxin related gene A (cytotoxin-associated gene A, CagA). One of the important virulence factors is that the positive strain is more dangerous than the negative strain after infection. The strain with CagA gene is an important pathogenic strain in H.pylori,.CagA is a protein encoded by the CagA gene on the CAG pathogenic island of H.pylori (cag pathogenicity island, CAG PAI). The CagA "injection" of the host cell is the only protein that H.pylori can enter the host cell. The latest evidence-based evidence suggests that the CagA~+H.pylori strain increases the risk of gastric cancer, and the incidence of gastric cancer is significantly increased in.CagA transgenic mice. CagA is the key molecule to promote the occurrence of gastric cancer. Cancer stem cells (CSCs) theory holds that there are a small group of cell groups with stem cell properties in the tumor tissue, with unlimited self renewal and the ability to induce tumorigenesis. It is the seed cell produced by the tumor. Because of its high metastatic potential and resistance to radiotherapy and chemotherapy, it is considered to be malignant. The study of H.pylori has focused on its role in promoting the proliferation of gastric cancer cells and inhibiting the apoptosis of gastric cancer cells. However, the latest research has found that CagA~+H.pylori can induce the epithelial mesenchymal transition (epithelial mesenchymal transition, EMT) in gastric cancer cells to make gastric cancer cells This subject further confirms the role of CagA~+h.pylori in promoting the enhancement of the dry character of gastric cancer cells and clarifies its mechanism. Therefore, this topic enriches the pathogenesis of CagA~+h.pylori infection, and helps to deepen the understanding of the role of CagA~+h.pylori in the development of gastric cancer and to eradicate CagA~+h.pyl specifically. Ori provides new theoretical basis. [Objective] 1 to construct a H.pylori infected gastric cancer cell model, evaluate the effect of CagA~+h.pylori on the dry characteristics of gastric cancer cells; 2, to explore the molecular mechanism of the enhancement of the dry character of gastric cancer cells by CagA~+h.pylori. [method] 1, to evaluate the effect of CagA ~+h.pylori on the dry character of gastric cancer cells: (1) A model of H.pylori infection of gastric cancer cells was built; (2) through flow cytometry, the proportion of CagA~+h.pylori (H.pylori strain NCTC11637) infection group, caga-h.pylori (H.pylori strain NCTC11637 as the background CagA knockout) and the gastric cancer stem cell surface markers positive in the uninfected group were measured, and (3) from PCR from mRNA. The transcriptional level of the surface markers of gastric cancer stem cells in the above groups was further analyzed. (4) the in vitro ability of gastric cancer cells in the above groups was evaluated by the in vitro test. (5) the expression level of the dry transcription factors of gastric carcinoma in all the groups was detected by westernblotting (WB); (6) the above observation was observed under the light microscope. The morphological changes of gastric cancer cells in the group and the change of the expression of EMT markers by WB,.2, to explore the molecular mechanism of enhancing the dry character of gastric cancer cells by CagA~+h.pylori: (1) the localization of beta -catenin in the above gastric cancer cells was observed by the immunofluorescence test, and (2) the double luciferase reporter gene experiment was carried out. The activation level of wnt/ beta -catenin signaling pathway in all the gastric cancer cells was detected. (3) the expression level of ser675 and ser552 of CagA~+h.pylori and caga-h.pylori infected gastric cancer cells at different phase point beta -catenin nuclear transposition sites was detected by WB; (4) su11274 and pi3k/akt inhibitor gsk690693 were pre placed respectively. In gastric cancer cells, the phosphorylation level of ser675 and ser552 loci of beta -catenin in gastric cancer cells after CagA~+h.pylori infection was further detected by WB. (5) gastric cancer cells were pretreated with wnt/ beta -catenin inhibitor xav, and the gastric cancer stem cells in gastric cancer cells were detected by flow cytometry, PCR and ball formation test. The proportion of gastric cancer cells with positive surface markers, the surface marker mRNA level of gastric cancer stem cells and the ability of gastric cancer cells to form the ball; (6) the gastric cancer cells were pretreated with the wnt/ beta -catenin inhibitor xav, and the expression level of Nanog and Oct4 protein of the dry transcription factors in gastric cancer cells and m were detected by WB and PCR respectively. The effect of RNA level; (7) to construct a double luciferase reporter plasmid of Nanog and Oct4 promoter region, and to detect the effect of CagA~+h.pylori mediated beta -catenin nuclear transposition on the activity of Nanog and Oct4 promoter through double luciferase reporter assay; (8) bioinformatics predicts the possible binding area of beta -catenin on Nanog and Oct4 promoters by staining. The chromatinimmunoprecipitation (chip) test was used to detect the effect of beta -catenin on the promoter of Nanog and Oct4. (9) through the C13 exhalation test and the detection of CagA antibody in the serum, the gastric cancer patients were divided into CagA~+h.pylori infection group and caga-h.pylori infection group, and the nano of the two groups of gastric cancer tissue specimens were detected respectively. G and Oct4 protein expression level and mRNA level. [results] 1, CagA~+h.pylori infected gastric cancer cells, compared with the caga-h.pylori infection group and the uninfected group, more gastric cancer cells showed the gastric cancer stem cell like characteristics; 2, CagA~+h.pylori activated wnt/ beta -catenin signaling pathway, including the promotion of beta -catenin nuclear translocation and enhanced beta -cateni. The transcriptional activity of N; 3, CagA~+h.pylori through c-met and / or Akt mediated pathway to promote the phosphorylation of ser675 and ser552 loci at the end of beta -cateninc, and the nuclear transposition of the beta -catenin; 4, the activation of the wnt/ beta -catenin signaling pathway is a critical link in the enhancement of the dry character of gastric cancer cells; 5, activation of the wnt/ beta signaling pathway is involved in the activation of the pathway. AgA~+h.pylori up-regulated the dry transcription factors Nanog and Oct4; 6, CagA~+h.pylori infected gastric cancer patients, compared with caga-h.pylori infected gastric cancer patients, the expression of Nanog and Oct4 in gastric cancer tissues increased significantly. [Conclusion] CagA~+h.pylori promotes the expression of Nanog and Oct4, and promotes gastric cancer cell stem by activating the wnt/ beta -catenin signaling pathway. At present, both domestic and foreign guidelines recommend the treatment of high risk people (chronic atrophic gastritis, ulcers, intestinal metaplasia, dysplasia and gastric cancer) to eradicate H.pylori, but its molecular mechanism is not clear. This topic confirms that the high virulent strain in H.pylori, CagA~+h.pylori, can promote gastric cancer. The enhancement of cell dry characteristics may be an important cause of gastric mucosal epithelial cells from abnormal proliferation to final development of gastric cancer. It may also be an important reason for the recurrence and metastasis of gastric cancer cells after gastric cancer eradication. Therefore, this topic provides a new perspective for understanding and understanding the pathogenesis of H.pylori infection. It is helpful to deepen the understanding of the role of CagA~+H.pylori in the occurrence and development of gastric cancer and provide a new theoretical basis for the specific eradication of CagA~+H.pylori.
【学位授予单位】：第三军医大学
【学位级别】：博士
【学位授予年份】：2016
【分类号】：R735.2
本文编号：2156442
[Abstract]:Gastric cancer is one of the main malignant tumors that harm human health. The incidence and mortality of global gastric cancer are high. According to the latest statistics, the incidence and mortality of gastric cancer in China are second in all tumors, and the number of people dying of gastric cancer is up to 500 thousand every year. At present, the infection rate of Helicobacter pylori (H.pylor) is about 50% in the world, and in some regions up to 80% (Management of Helicobacter pylori infection-the Maastricht IV/Florence Consensus Report, 2012). In China, the infection rate is also high, and the infection rate in adults is fourth times. The national consensus report on the treatment of Helicobacter pylori infection, 2012), WHO has been listed as a class I carcinogen of gastric cancer as early as 1994. Although the infection rate of H.pylori in the population is very high, only some of the infected people eventually develop into gastric cancer. The cause of the infection is the pathogenicity of H.pylori and the species of its strains, host genetic factors and environmental factors. The difference in the type of.H.pylori isolates is an important cause of different clinical outcomes. The European Maastricht consensus in.2012 is that the occurrence and development of gastric cancer are affected by H.pylori virulence factors, and the evidence level of evidence-based medicine is the CagA protein encoded by the 1a. cytotoxin related gene A (cytotoxin-associated gene A, CagA). One of the important virulence factors is that the positive strain is more dangerous than the negative strain after infection. The strain with CagA gene is an important pathogenic strain in H.pylori,.CagA is a protein encoded by the CagA gene on the CAG pathogenic island of H.pylori (cag pathogenicity island, CAG PAI). The CagA "injection" of the host cell is the only protein that H.pylori can enter the host cell. The latest evidence-based evidence suggests that the CagA~+H.pylori strain increases the risk of gastric cancer, and the incidence of gastric cancer is significantly increased in.CagA transgenic mice. CagA is the key molecule to promote the occurrence of gastric cancer. Cancer stem cells (CSCs) theory holds that there are a small group of cell groups with stem cell properties in the tumor tissue, with unlimited self renewal and the ability to induce tumorigenesis. It is the seed cell produced by the tumor. Because of its high metastatic potential and resistance to radiotherapy and chemotherapy, it is considered to be malignant. The study of H.pylori has focused on its role in promoting the proliferation of gastric cancer cells and inhibiting the apoptosis of gastric cancer cells. However, the latest research has found that CagA~+H.pylori can induce the epithelial mesenchymal transition (epithelial mesenchymal transition, EMT) in gastric cancer cells to make gastric cancer cells This subject further confirms the role of CagA~+h.pylori in promoting the enhancement of the dry character of gastric cancer cells and clarifies its mechanism. Therefore, this topic enriches the pathogenesis of CagA~+h.pylori infection, and helps to deepen the understanding of the role of CagA~+h.pylori in the development of gastric cancer and to eradicate CagA~+h.pyl specifically. Ori provides new theoretical basis. [Objective] 1 to construct a H.pylori infected gastric cancer cell model, evaluate the effect of CagA~+h.pylori on the dry characteristics of gastric cancer cells; 2, to explore the molecular mechanism of the enhancement of the dry character of gastric cancer cells by CagA~+h.pylori. [method] 1, to evaluate the effect of CagA ~+h.pylori on the dry character of gastric cancer cells: (1) A model of H.pylori infection of gastric cancer cells was built; (2) through flow cytometry, the proportion of CagA~+h.pylori (H.pylori strain NCTC11637) infection group, caga-h.pylori (H.pylori strain NCTC11637 as the background CagA knockout) and the gastric cancer stem cell surface markers positive in the uninfected group were measured, and (3) from PCR from mRNA. The transcriptional level of the surface markers of gastric cancer stem cells in the above groups was further analyzed. (4) the in vitro ability of gastric cancer cells in the above groups was evaluated by the in vitro test. (5) the expression level of the dry transcription factors of gastric carcinoma in all the groups was detected by westernblotting (WB); (6) the above observation was observed under the light microscope. The morphological changes of gastric cancer cells in the group and the change of the expression of EMT markers by WB,.2, to explore the molecular mechanism of enhancing the dry character of gastric cancer cells by CagA~+h.pylori: (1) the localization of beta -catenin in the above gastric cancer cells was observed by the immunofluorescence test, and (2) the double luciferase reporter gene experiment was carried out. The activation level of wnt/ beta -catenin signaling pathway in all the gastric cancer cells was detected. (3) the expression level of ser675 and ser552 of CagA~+h.pylori and caga-h.pylori infected gastric cancer cells at different phase point beta -catenin nuclear transposition sites was detected by WB; (4) su11274 and pi3k/akt inhibitor gsk690693 were pre placed respectively. In gastric cancer cells, the phosphorylation level of ser675 and ser552 loci of beta -catenin in gastric cancer cells after CagA~+h.pylori infection was further detected by WB. (5) gastric cancer cells were pretreated with wnt/ beta -catenin inhibitor xav, and the gastric cancer stem cells in gastric cancer cells were detected by flow cytometry, PCR and ball formation test. The proportion of gastric cancer cells with positive surface markers, the surface marker mRNA level of gastric cancer stem cells and the ability of gastric cancer cells to form the ball; (6) the gastric cancer cells were pretreated with the wnt/ beta -catenin inhibitor xav, and the expression level of Nanog and Oct4 protein of the dry transcription factors in gastric cancer cells and m were detected by WB and PCR respectively. The effect of RNA level; (7) to construct a double luciferase reporter plasmid of Nanog and Oct4 promoter region, and to detect the effect of CagA~+h.pylori mediated beta -catenin nuclear transposition on the activity of Nanog and Oct4 promoter through double luciferase reporter assay; (8) bioinformatics predicts the possible binding area of beta -catenin on Nanog and Oct4 promoters by staining. The chromatinimmunoprecipitation (chip) test was used to detect the effect of beta -catenin on the promoter of Nanog and Oct4. (9) through the C13 exhalation test and the detection of CagA antibody in the serum, the gastric cancer patients were divided into CagA~+h.pylori infection group and caga-h.pylori infection group, and the nano of the two groups of gastric cancer tissue specimens were detected respectively. G and Oct4 protein expression level and mRNA level. [results] 1, CagA~+h.pylori infected gastric cancer cells, compared with the caga-h.pylori infection group and the uninfected group, more gastric cancer cells showed the gastric cancer stem cell like characteristics; 2, CagA~+h.pylori activated wnt/ beta -catenin signaling pathway, including the promotion of beta -catenin nuclear translocation and enhanced beta -cateni. The transcriptional activity of N; 3, CagA~+h.pylori through c-met and / or Akt mediated pathway to promote the phosphorylation of ser675 and ser552 loci at the end of beta -cateninc, and the nuclear transposition of the beta -catenin; 4, the activation of the wnt/ beta -catenin signaling pathway is a critical link in the enhancement of the dry character of gastric cancer cells; 5, activation of the wnt/ beta signaling pathway is involved in the activation of the pathway. AgA~+h.pylori up-regulated the dry transcription factors Nanog and Oct4; 6, CagA~+h.pylori infected gastric cancer patients, compared with caga-h.pylori infected gastric cancer patients, the expression of Nanog and Oct4 in gastric cancer tissues increased significantly. [Conclusion] CagA~+h.pylori promotes the expression of Nanog and Oct4, and promotes gastric cancer cell stem by activating the wnt/ beta -catenin signaling pathway. At present, both domestic and foreign guidelines recommend the treatment of high risk people (chronic atrophic gastritis, ulcers, intestinal metaplasia, dysplasia and gastric cancer) to eradicate H.pylori, but its molecular mechanism is not clear. This topic confirms that the high virulent strain in H.pylori, CagA~+h.pylori, can promote gastric cancer. The enhancement of cell dry characteristics may be an important cause of gastric mucosal epithelial cells from abnormal proliferation to final development of gastric cancer. It may also be an important reason for the recurrence and metastasis of gastric cancer cells after gastric cancer eradication. Therefore, this topic provides a new perspective for understanding and understanding the pathogenesis of H.pylori infection. It is helpful to deepen the understanding of the role of CagA~+H.pylori in the occurrence and development of gastric cancer and provide a new theoretical basis for the specific eradication of CagA~+H.pylori.
【学位授予单位】：第三军医大学
【学位级别】：博士
【学位授予年份】：2016
【分类号】：R735.2
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