【摘要】：胃癌是危害人類健康的主要惡性腫瘤之一,全球胃癌的發(fā)病率和死亡率居高不下。據(jù)最新的統(tǒng)計數(shù)據(jù)表明,我國胃癌的發(fā)病率和死亡率在所有腫瘤中均居第二位,每年死于胃癌的人數(shù)高達50萬。因此,研究影響胃癌發(fā)生發(fā)展的因素具有重要意義。目前,世界范圍內(nèi)幽門螺桿菌(Helicobacter pylori,H.pylor)的感染率約50%,部分地區(qū)高達80%(Management of Helicobacter pylori infection-the Maastricht IV/Florence Consensus Report,2012)。在我國,H.pylori的感染率總體上也很高,成人中感染率達40-60%(第四次全國幽門螺桿菌感染處理共識報告,2012),WHO早在1994年就已將其列為胃癌的Ⅰ類致癌因子。雖然H.pylori在人群中的感染率很高,但只有部分感染者最終發(fā)展為胃癌,究其原因,H.pylori的致病性與其菌株的種類、宿主遺傳因素及環(huán)境因素等有關(guān)。H.pylori菌株類型的不同是導(dǎo)致不同臨床結(jié)局的重要原因。2012年歐洲馬斯特里赫特共識中提到,胃癌的發(fā)生發(fā)展受H.pylori毒力因子的影響,其循證醫(yī)學(xué)的證據(jù)等級為1a。細胞毒素相關(guān)基因A(cytotoxin-associated gene A,CagA)編碼的CagA蛋白作為重要的毒力因子之一,其陽性菌株感染后導(dǎo)致嚴重臨床后果的危險性明顯大于陰性菌株,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致病島(cag pathogenicity island,cag PAI)上CagA基因編碼的蛋白,通過cag PAI編碼Ⅳ型分泌系統(tǒng)將CagA“注入”宿主細胞,是H.pylori唯一能進入宿主細胞而發(fā)揮生物學(xué)作用的蛋白。最新的循證醫(yī)學(xué)證據(jù)表明,CagA~+H.pylori菌株增加胃癌發(fā)生的風(fēng)險。CagA轉(zhuǎn)基因小鼠的胃癌發(fā)生率明顯增加,證實CagA是促進胃癌發(fā)生的關(guān)鍵分子。腫瘤干細胞(cancer stem cells,CSCs)學(xué)說認為腫瘤組織中存在一小部分具有干細胞性質(zhì)的細胞群體,具有無限的自我更新和誘導(dǎo)腫瘤發(fā)生的能力,是腫瘤產(chǎn)生的種子細胞,由于其同時具有高轉(zhuǎn)移潛能、對放化療等治療抵抗等特性,而被認為是惡性腫瘤復(fù)發(fā)轉(zhuǎn)移的關(guān)鍵。以往有關(guān)H.pylori的研究主要集中于其在促進胃癌細胞增殖和抑制胃癌細胞凋亡中的作用。但最新的研究發(fā)現(xiàn),CagA~+H.pylori可以通過誘導(dǎo)胃癌細胞發(fā)生上皮-間葉轉(zhuǎn)化(epithelial mesenchymal transition,EMT),從而使胃癌細胞獲得胃癌干細胞特征。本課題進一步確認CagA~+h.pylori在促胃癌細胞干性特征增強中的作用,并闡明其機制。因此,本課題豐富了CagA~+h.pylori菌株感染的致病機理,有助于加深CagA~+h.pylori在胃癌發(fā)生發(fā)展中作用的認識,為特異性根除CagA~+h.pylori提供新的理論依據(jù)�！狙芯磕康摹�1、構(gòu)建h.pylori感染胃癌細胞模型,評價CagA~+h.pylori對胃癌細胞干性特征的影響;2、探討CagA~+h.pylori促胃癌細胞干性特征增強的分子機制�！狙芯糠椒ā�1、評價CagA~+h.pylori對胃癌細胞干性特征的影響:(1)構(gòu)建h.pylori感染胃癌細胞的模型;(2)通過流式細胞技術(shù),分別檢測CagA~+h.pylori(h.pylori菌株nctc11637)感染組、caga-h.pylori(以h.pylori菌株nctc11637為背景的caga敲除株)感染組及未感染組中胃癌干細胞表面標志物陽性的胃癌細胞比例;(3)通過pcr從mrna水平進一步分析上述各組中胃癌干細胞表面標志物的轉(zhuǎn)錄水平;(4)通過體外成球?qū)嶒炘u價上述各組中胃癌細胞的體外成球能力;(5)通過免疫印記(westernblotting,wb)檢測上述各組中胃癌細胞干性轉(zhuǎn)錄因子的表達水平;(6)光鏡下觀察上述各組中胃癌細胞形態(tài)學(xué)的改變,wb檢測emt標志物的表達變化。2、探討CagA~+h.pylori促胃癌細胞干性特征增強的分子機制:(1)通過免疫熒光實驗,在激光共聚焦下觀察β-catenin在上述各組胃癌細胞中的定位情況;(2)通過雙熒光素酶報告基因?qū)嶒灆z測上述各組胃癌細胞中wnt/β-catenin信號通路的活化水平;(3)通過wb檢測CagA~+h.pylori及caga-h.pylori感染胃癌細胞不同時相點β-catenin核轉(zhuǎn)位關(guān)鍵磷酸化位點ser675和ser552的表達水平;(4)使用c-met抑制劑su11274及pi3k/akt抑制劑gsk690693分別預(yù)處理胃癌細胞,通過wb進一步檢測CagA~+h.pylori感染后胃癌細胞中β-catenin的ser675和ser552位點磷酸化水平;(5)使用wnt/β-catenin抑制劑xav預(yù)處理胃癌細胞,通過流式細胞技術(shù)、pcr以及成球?qū)嶒?分別檢測CagA~+h.pylori的感染對胃癌細胞中胃癌干細胞表面標志物陽性的胃癌細胞比例、胃癌干細胞表面標志物mrna水平以及胃癌細胞成球能力的影響;(6)使用wnt/β-catenin抑制劑xav預(yù)處理胃癌細胞,通過wb和pcr分別檢測CagA~+h.pylori的感染對胃癌細胞中干性轉(zhuǎn)錄因子nanog和oct4蛋白表達水平及mrna水平的影響;(7)構(gòu)建nanog和oct4啟動子區(qū)域的雙熒光素酶報告質(zhì)粒,通過雙熒光素酶報告實驗檢測CagA~+h.pylori介導(dǎo)的β-catenin核轉(zhuǎn)位對nanog和oct4啟動子活性的影響;(8)生物信息學(xué)預(yù)測β-catenin在nanog和oct4啟動子上的可能結(jié)合區(qū)域,通過染色質(zhì)免疫共沉淀(chromatinimmunoprecipitation,chip)實驗檢測β-catenin作用于nanog和oct4啟動子的區(qū)域;(9)通過c13尿素酶呼氣試驗及檢測血清中caga抗體,將胃癌患者分為CagA~+h.pylori感染組及caga-h.pylori感染組,分別檢測兩組患者胃癌組織標本中nanog和oct4蛋白表達水平及mrna水平。【研究結(jié)果】1、CagA~+h.pylori感染的胃癌細胞,與caga-h.pylori感染組及未感染組相比,更多的胃癌細胞表現(xiàn)出胃癌干細胞樣特征;2、CagA~+h.pylori活化wnt/β-catenin信號通路,包括促進β-catenin的核轉(zhuǎn)位及增強β-catenin的轉(zhuǎn)錄活性;3、CagA~+h.pylori通過c-met和/或akt介導(dǎo)的通路促β-cateninc末端ser675和ser552位點的磷酸化,使β-catenin發(fā)生核轉(zhuǎn)位;4、wnt/β-catenin信號通路的活化是CagA~+h.pylori促胃癌細胞干性特征增強的重要環(huán)節(jié);5、wnt/β-catenin信號通路的活化參與CagA~+h.pylori上調(diào)干性轉(zhuǎn)錄因子nanog和oct4;6、CagA~+h.pylori感染的胃癌患者,與caga-h.pylori感染的胃癌患者相比,胃癌組織標本中nanog和oct4的表達明顯增加�！窘Y(jié)論】CagA~+h.pylori通過活化wnt/β-catenin信號通路,上調(diào)nanog和oct4的表達,促胃癌細胞干性特征增強。【研究意義】目前,國內(nèi)外指南均推薦高風(fēng)險人群(慢性萎縮性胃炎、潰瘍、腸上皮化生、異型增生及胃癌術(shù)后等)根除h.pylori的治療,但其分子機制并不清楚。本課題證實h.pylori中的高毒力致病菌株——CagA~+h.pylori可以促胃癌細胞干性特征增強,這可能是胃粘膜上皮細胞從異常增生到最終發(fā)展為胃癌的重要原因,也可能是胃癌根除術(shù)后少數(shù)殘余胃癌細胞致胃癌復(fù)發(fā)轉(zhuǎn)移的重要原因。因此,本課題為深入理解和認識H.pylori感染的致病機制提供了新的視角,有助于加深CagA~+H.pylori在胃癌發(fā)生發(fā)展中作用的認識,為特異性根除CagA~+H.pylori提供新的理論依據(jù)。
[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.
【學(xué)位授予單位】：第三軍醫(yī)大學(xué)
【學(xué)位級別】：博士
【學(xué)位授予年份】：2016
【分類號】：R735.2

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