本文選題：非編碼 + RNA　； 參考：《大連醫(yī)科大學(xué)》2016年博士論文

【摘要】：一般認(rèn)為,幽門螺桿菌(Helicobacter pylori,H.pylori)導(dǎo)致胃癌的發(fā)病機(jī)理是由其觸發(fā)的炎癥引起的胃萎縮、腸上皮化生、異型增生并最終發(fā)展成腺癌的一個(gè)多級(jí)發(fā)展過程。H.pylori感染引起胃炎和胃萎縮,是促成癌前病變和最終導(dǎo)致胃癌的重要因素。機(jī)體對(duì)于H.pylori感染能夠產(chǎn)生免疫應(yīng)答,但是并不能完全有效地清除H.pylori。H.pylori對(duì)宿主的毒性作用、免疫逃逸作用以及宿主對(duì)H.pylori的殺滅清除作用存在著有機(jī)的動(dòng)態(tài)平衡,但這種平衡的分子機(jī)制尚不明確。非編碼RNA,即不能編碼蛋白質(zhì)的RNA,包括核糖體RNA(r RNA),轉(zhuǎn)運(yùn)RNA(t RNA),小干擾RNA(siRNA),核內(nèi)小RNA(snRNA),核仁小RNA(small nuclear RNA,sno RNA),微小RNA(microRNA),piwi相互作用RNA(piwi-interacting RNAs,piRNA)及長(zhǎng)鏈非編碼RNA(long noncoding RNA,lncRNA)等多種RNA,其中大部分RNA的功能是已知的,但也有相當(dāng)一部分的RNA類型,具有特殊的結(jié)構(gòu),其功能也沒有得到廣泛的研究。這些RNA的共同特點(diǎn)是都能從基因組上轉(zhuǎn)錄而來(lái),但是不翻譯成蛋白,在RNA水平上就能行使各自的生物學(xué)功能了。從不同層面調(diào)控基因表達(dá)的非編碼RNA,根據(jù)分子長(zhǎng)度劃分為microRNA及l(fā)ncRNA。目前約有8000多種microRNA得到鑒定,其中1500多種microRNA在哺乳動(dòng)物體內(nèi)表達(dá)。在人類基因組中已經(jīng)明確標(biāo)定的lncRNA有9640種。microRNA是一類帶有18-24個(gè)核苷酸的RNA,影響多種基因的轉(zhuǎn)錄和表達(dá),在炎癥、細(xì)胞增殖、細(xì)胞凋亡和變異中起著重要作用。lncRNA在近年的研究中得到了極大的關(guān)注,越來(lái)越多的學(xué)者和實(shí)驗(yàn)室致力于研究其結(jié)構(gòu)和功能。大多數(shù)的lncRNA參與的生物學(xué)功能包括基因印記、染色體修飾、蛋白質(zhì)結(jié)合與干擾等,也有部分lncRNA行使其功能與microRNA相類似,通過激活或干擾轉(zhuǎn)錄本,實(shí)現(xiàn)對(duì)某個(gè)特定蛋白的靶向激活或抑制。同時(shí),還有大量的lncRNA尚未知其功能。本研究通過H.pylori感染人胃上皮細(xì)胞模型,利用全基因組測(cè)序技術(shù)檢測(cè)H.pylori感染前后胃上皮細(xì)胞的lncRNA表達(dá)譜變化,結(jié)合實(shí)時(shí)定量PCR,對(duì)差異lncRNA進(jìn)行篩選與鑒定。選取差異表達(dá)最明顯的XLOC_004122和XLOC_014388,檢測(cè)其在臨床H.pylori感染組織樣本的表達(dá)特性,并探討其與致腫瘤預(yù)后指標(biāo)是否存在相關(guān)性。同時(shí),針對(duì)同樣差異表達(dá)的microRNA-146a和microRNA-99b,通過靶點(diǎn)鑒定和功能分析等手段,深入研究其調(diào)控H.pylori感染的分子機(jī)制。本研究分為三部分:(一)幽門螺桿菌侵襲胃上皮細(xì)胞引起的長(zhǎng)鏈非編碼RNA差異表達(dá)分析;(二)microRNA-146a靶向COX-2調(diào)控H.pylori引起胃癌細(xì)胞凋亡的研究;(三)microRNA-99b在胃癌上皮細(xì)胞中通過調(diào)控自噬發(fā)生抑制H.pylori感染及細(xì)胞增殖作用研究。第一部分 幽門螺桿菌侵襲胃上皮細(xì)胞引起的長(zhǎng)鏈非編碼RNA差異表達(dá)分析本實(shí)驗(yàn)利用H.pylor感染人胃上皮GES-1細(xì)胞24小時(shí)后,提取細(xì)胞的total RNA,利用全基因組測(cè)序手段,篩選鑒定差異表達(dá)的lncRNA分子;收集臨床病人胃上皮組織樣本,應(yīng)用Realtime RT-PCR技術(shù)檢測(cè)lncRNA分子在H.pylor感染病人和非感染病人中的表達(dá)規(guī)律,探討lncRNA分子在H.pylor致癌發(fā)生、發(fā)展的關(guān)系及其在臨床預(yù)后判斷中的應(yīng)用意義。同時(shí),利用GO分析及基因共表達(dá)分析等生物信息學(xué)分析手段,探索差異表達(dá)的lncRNA的生物學(xué)功能。結(jié)果顯示,H.pylori感染引起GES-1細(xì)胞一系列非編碼RNA的表達(dá)改變,其中表達(dá)上調(diào)的有24條lncRNA,表達(dá)下調(diào)的有22條lncRNA。其中五條lncRNA,XLOC_004562(p0.05),XLOC_005912,XLOC_000620,XLOC_004122(p0.05)和XLOC_014388(p0.05)的表達(dá)差異最顯著,并已被PCR結(jié)果證實(shí)。同時(shí)發(fā)現(xiàn),XLOC_004122和XLOC_014388在臨床H.pylori感染的組織樣本中顯著差異表達(dá),差異具有統(tǒng)計(jì)學(xué)意義,且與腸化生現(xiàn)象成線性相關(guān)性(p0.05)。這提示這兩段基因在臨床治療及預(yù)后方面可能存在標(biāo)志物的功能。GO分析和共表達(dá)分析發(fā)現(xiàn),XLOC_004122共表達(dá)主要包括膜蛋白組份、跨膜蛋白、離子通道等相應(yīng)功能的基因,這說明XLOC_004122可能參與H.pylori被細(xì)胞胞吞的過程;XLOC_014388共表達(dá)的主要包括細(xì)胞間的信號(hào)傳遞、激酶活性、神經(jīng)發(fā)育等功能的基因。本研究的意義在于我們可能發(fā)現(xiàn)了治療H.pylori感染及預(yù)防其癌變的新方法,有廣闊的臨床應(yīng)用前景。第二部分 microRNA-146a靶向COX-2調(diào)控H.pylori引起胃癌細(xì)胞凋亡的研究本實(shí)驗(yàn)通過向H.pylori感染的胃癌細(xì)胞MKN7轉(zhuǎn)染microRNA-146a mimics和inhibitor,建立microRNA-146a過表達(dá)及抑制表達(dá)的細(xì)胞模型,利用V-Fluos staining kit(凋亡檢測(cè)試劑盒)測(cè)定細(xì)胞凋亡率,結(jié)合凋亡正相關(guān)標(biāo)志物Bax和負(fù)相關(guān)標(biāo)志物Bcl-2的表達(dá),確定microRNA-146a是否可以影響癌細(xì)胞的發(fā)生并深入探討microRNA-146a對(duì)癌細(xì)胞的凋亡發(fā)生影響是否通過抑制靶基因COX-2實(shí)現(xiàn)。同時(shí),檢測(cè)胃癌臨床樣本中,microRNA-146a表達(dá)與凋亡發(fā)生率的相關(guān)性并分析microRNA-146a與腫瘤預(yù)后的相關(guān)性。結(jié)果顯示:H.pylori感染的癌細(xì)胞模型和臨床樣本中,microRNA-146a表達(dá)(p0.05)和細(xì)胞凋亡發(fā)生率(p0.05)均顯著高于H.pylori陰性對(duì)照組;microRNA-146a過表達(dá)的腫瘤細(xì)胞較對(duì)照組凋亡率顯著升高(p0.05),且凋亡正相關(guān)分子Bax顯著上調(diào)(p0.05),負(fù)相關(guān)分子Bcl-2顯著下調(diào)(p0.05);在此細(xì)胞模型中,對(duì)COX-2的過表達(dá)可抑制microRNA-146a對(duì)凋亡的上調(diào)作用(p0.05),說明microRNA-146a對(duì)細(xì)胞凋亡的調(diào)控是通過靶向抑制COX-2的表達(dá)實(shí)現(xiàn)的。進(jìn)一步的臨床樣本分析發(fā)現(xiàn),microRNA-146a與腫瘤組織細(xì)胞凋亡率正相關(guān),且與腫瘤的淋巴轉(zhuǎn)移具有顯著相關(guān)性(p0.05)。本實(shí)驗(yàn)結(jié)果說明microRNA-146a可能通過調(diào)控COX-2表達(dá),促進(jìn)凋亡,進(jìn)而抑制H.pylori感染引起的胃癌發(fā)生。這部分研究的發(fā)現(xiàn)進(jìn)一步闡明H.pylori感染的致癌發(fā)生機(jī)制以及機(jī)體對(duì)H.pylori的致癌作用調(diào)節(jié)機(jī)制研究提供新的方向。第三部分 microRNA-99b在胃癌上皮細(xì)胞中通過調(diào)控自噬發(fā)生抑制H.pylori感染及細(xì)胞增殖作用研究本實(shí)驗(yàn)在H.pylori感染的胃癌細(xì)胞模型和臨床樣本中,檢測(cè)microRNA-99b的表達(dá)。通過向H.pylori感染的胃癌細(xì)胞轉(zhuǎn)染microRNA-99b mimics和inhibitor,建立microRNA-99b過表達(dá)及抑制表達(dá)的細(xì)胞模型,檢測(cè)細(xì)胞內(nèi)H.pylori菌荷菌量的變化;利用Western blot檢測(cè)自噬相關(guān)蛋白LC3-II,轉(zhuǎn)染GFP-LC3并利用激光共聚焦技術(shù)對(duì)LC3進(jìn)行斑點(diǎn)計(jì)數(shù),從而判定microRNA-99b是否可以調(diào)控自噬發(fā)生;同時(shí),利用生物信息學(xué)軟件預(yù)測(cè)microRNA-99b的靶基因,并通過靶基因熒光素酶報(bào)告基因?qū)嶒?yàn),鑒定microRNA-99b的靶基因并分析microRNA-99b調(diào)控自噬的分子機(jī)制是否通過抑制靶基因?qū)崿F(xiàn)的。結(jié)果顯示,H.pylori感染的胃癌細(xì)胞模型和臨床樣本中,microRNA-99b表達(dá)(p0.05)顯著高于H.pylori陰性對(duì)照組;microRNA-99b過表達(dá)的腫瘤細(xì)胞對(duì)H.pylori的殺菌作用強(qiáng)于對(duì)照組,結(jié)果具有統(tǒng)計(jì)學(xué)意義(p0.05);Western blot結(jié)果顯示,LC3分子由LC3-I向LC3-II轉(zhuǎn)化,說明microRNA-99b過表達(dá)可誘導(dǎo)細(xì)胞自噬的發(fā)生,對(duì)LC3斑點(diǎn)計(jì)數(shù)也印證了這一點(diǎn)(p0.05);利用targetscan軟件預(yù)測(cè)到microRNA-99b的靶基因?yàn)閙 TOR。熒光素酶報(bào)告基因?qū)嶒?yàn)證實(shí)了microRNA-99b確實(shí)能與m TOR的3′-UTR結(jié)合;Western blot結(jié)果表明,microRNA-99b通過抑制m TOR蛋白表達(dá)促進(jìn)自噬的發(fā)生。結(jié)論:綜合本文的發(fā)現(xiàn)及相關(guān)數(shù)據(jù),我們提出以下結(jié)論:1.篩選鑒定出H.pylori感染引起的差異表達(dá)的長(zhǎng)鏈非編碼RNA,并發(fā)現(xiàn)XLOC_004122和XLOC_014388在臨床H.pylori感染的組織樣本中顯著差異表達(dá),且與腸化生現(xiàn)象成線性相關(guān)性。提示這兩段基因在臨床治療及預(yù)后方面可能存在標(biāo)志物的功能。2.發(fā)現(xiàn)microRNA-146a在H.pylori感染中調(diào)控細(xì)胞的凋亡和癌變,并證實(shí)是通過靶向COX-2實(shí)現(xiàn)此功能。microRNA-146a也與胃癌的淋巴轉(zhuǎn)移正相關(guān)。3.發(fā)現(xiàn)microRNA-99b在H.pylori感染中刺激細(xì)胞自噬發(fā)生并因此上調(diào)細(xì)胞殺菌能力。此功能是通過靶向抑制m TOR蛋白的功能實(shí)現(xiàn)的。
[Abstract]:It is generally believed that the pathogenesis of Helicobacter pylori (H.pylori) causes gastric atrophy caused by inflammation, intestinal metaplasia, dysplasia and eventually a multistage development of adenocarcinoma..H.pylori infection causes gastritis and gastric atrophy, which is important for leading to precancerous lesions and ultimately leading to gastric cancer. Factors. The body can produce an immune response to H.pylori infection, but it can not completely effectively eliminate the toxic effect of H.pylori.H.pylori on the host, the immune escape effect and the host's killing and scavenging effect on H.pylori, but the molecular mechanism of this balance is not clear. Non coded RNA, that is, can not be made up. RNA, including the ribosome RNA (R RNA), transshipment RNA (t RNA), small interference RNA (siRNA), small RNA (snRNA), small nucleolar RNA, and long chain non coding traditions, etc. It is known, but there are a considerable number of RNA types, with special structures, and their functions are not widely studied. The common characteristics of these RNA are to be transcribed from the genome, but not translated into proteins, and they can exercise their respective biological functions at the RNA level. The non coded R that regulates gene expression from different levels. NA, according to molecular length divided into microRNA and lncRNA., about 8000 kinds of microRNA have been identified, of which more than 1500 kinds of microRNA are expressed in mammals. In the human genome, 9640 kinds of.MicroRNA, which have been clearly demarcated in the human genome, are RNA with 18-24 nucleotides, affecting the transcription and expression of a variety of genes, and in inflammation. .lncRNA plays an important role in cell proliferation, apoptosis and mutation. More and more scholars and laboratories are working to study their structures and functions. Most of the biological functions of lncRNA include gene imprinting, chromosome modification, protein binding and interference, and some lncRNA lines. By activating or interfering with the transcriptional transcript, the function of the microRNA is activated or suppressed by activating or interfering with the transcriptional transcript. At the same time, a large number of lncRNA are still unknown. In this study, the human gastric epithelial cell model was infected by H.pylori and the whole genome sequencing technology was used to detect the lncRNA of the gastric epithelial cells before and after the H.pylori infection. The expression of lncRNA was screened and identified by real-time quantitative PCR. The most distinct XLOC_004122 and XLOC_014388 were selected, and the expression characteristics of the H.pylori infected tissue samples were detected, and the correlation with the tumor prognosis index was discussed. At the same time, the expression of the same differential microRNA-146a was also discussed. MicroRNA-99b, through target identification and functional analysis, the molecular mechanism of H.pylori infection control was studied in depth. This study was divided into three parts: (1) the differential expression analysis of long chain non coded RNA caused by Helicobacter pylori invasion of gastric epithelial cells; (two) the study of microRNA-146a targeting COX-2 to regulate the apoptosis of gastric cancer cells; Three) microRNA-99b in gastric epithelial cells by regulating autophagy to inhibit H.pylori infection and cell proliferation. First, Helicobacter pylori invasion of gastric epithelial cells caused by the long chain non coding RNA differential expression analysis of the experiment using H.pylor infected human gastric epithelial GES-1 24 hours after the extraction of GES-1 cells, the extraction of cell total RNA, Screening and identification of differentially expressed lncRNA molecules by whole genome sequencing, collecting samples of gastric epithelial tissue from clinical patients, using Realtime RT-PCR technique to detect the expression of lncRNA molecules in H.pylor infected patients and non infected patients, and to explore the relationship between the carcinogenesis of lncRNA molecules in H.pylor and the relationship between the development of the H.pylor and the clinical prognosis. At the same time, using GO analysis and gene co expression analysis and other bioinformatics analysis methods to explore the biological functions of differentially expressed lncRNA. The results show that H.pylori infection causes a series of non coded RNA expression changes in GES-1 cells, of which 24 lncRNA are up regulated, and 22 lncRNA. of five ln are down regulated. The difference in expression of cRNA, XLOC_004562 (P0.05), XLOC_005912, XLOC_000620, XLOC_004122 (P0.05) and XLOC_014388 (P0.05) is most significant and has been confirmed by PCR results. Meanwhile, the significant difference between XLOC_004122 and XLOC_014388 in the tissue samples infected by the clinic is found, and the difference is statistically significant and is linearly related to the intestinal metaplasia. P0.05. This suggests that the functional.GO analysis and co expression analysis of the two genes may exist in clinical treatment and prognosis. The co expression of XLOC_004122 mainly includes the genes of membrane protein, transmembrane protein, ion channel and so on, which indicates that XLOC_004122 may be involved in the process of H.pylori by cell endocytosis; XLOC_01 4388 co expression mainly includes genes of signaling, kinase activity, and nerve development among cells. The significance of this study is that we may find a new method for the treatment of H.pylori infection and the prevention of its carcinogenesis. The second part of the study has a broad prospect of clinical application. The second part of the target COX-2 regulates H.pylori to induce apoptosis of gastric cancer cells In this study, microRNA-146a mimics and inhibitor were transfected into the gastric cancer cell MKN7 infected with H.pylori, and the cell model of microRNA-146a overexpression and inhibition expression was established. The apoptosis rate of cells was measured by V-Fluos Staining Kit (apoptosis detection kit), and the expression of Bax and negative correlation markers Bcl-2 on the positive correlation marker of apoptosis was combined. Determine whether microRNA-146a can affect the occurrence of cancer cells and explore whether the effect of microRNA-146a on the apoptosis of cancer cells is realized by inhibiting the target gene COX-2. At the same time, the correlation between the expression of microRNA-146a and the incidence of apoptosis in the clinical samples of gastric cancer is detected and the correlation between the microRNA-146a and the prognosis of the tumor is analyzed. In the cancer cell model and clinical samples of H.pylori infection, microRNA-146a expression (P0.05) and apoptosis rate (P0.05) were significantly higher than those in the H.pylori negative control group; the apoptosis rate of microRNA-146a overexpressed tumor cells was significantly higher than that in the control group (P0.05), and the positive correlation molecule Bax increased significantly (P0.05), and the negative correlation molecule Bcl-2 showed Bcl-2. Down regulation (P0.05); in this cell model, overexpression of COX-2 inhibits the up-regulated action of microRNA-146a on apoptosis (P0.05), indicating that the regulation of microRNA-146a to cell apoptosis is achieved through the expression of target inhibition COX-2. Further clinical sample analysis shows that microRNA-146a is positively related to the apoptosis rate of tumor tissue and is associated with the apoptosis rate of the tumor tissue. The lymphatic metastasis of the tumor has a significant correlation (P0.05). The results of this study suggest that microRNA-146a may promote apoptosis by regulating COX-2 expression, and then inhibit the occurrence of gastric cancer caused by H.pylori infection. The findings of this study further elucidate the pathogenesis of H.pylori infection and the mechanism of the organism's regulatory mechanism for the carcinogenesis of H.pylori. The study provides a new direction. Part third microRNA-99b in gastric cancer epithelial cells through the regulation of autophagy inhibition of H.pylori infection and cell proliferation in this experiment in H.pylori infected gastric cancer cell model and clinical samples to detect the expression of microRNA-99b. Transfection of microRNA-99b MIM to H.pylori infected gastric cancer cells. ICs and inhibitor, a cell model of microRNA-99b overexpression and inhibition of expression was established to detect the changes in the amount of H.pylori bacteria in the cells; the autophagy related protein LC3-II was detected by Western blot, GFP-LC3 was transfected and the dot counting was used to determine LC3 by laser confocal technique, thus determining whether microRNA-99b could regulate autophagy; meanwhile, Using the bioinformatics software to predict the target gene of microRNA-99b, and identify the target gene of microRNA-99b by the target gene luciferase reporter gene test, and analyze whether the molecular mechanism of autophagy by microRNA-99b is realized by inhibiting the target gene. The results show that the gastric cancer cell model and clinical samples of H.pylori infection, microRNA-9 The expression of 9b (P0.05) was significantly higher than that of the H.pylori negative control group; the antiseptic effect of microRNA-99b overexpressed tumor cells on H.pylori was stronger than that of the control group, and the results were statistically significant (P0.05). The Western blot results showed that the LC3 molecules were converted from LC3-I to LC3-II, indicating that the expression of microRNA-99b over expression could induce autophagy. This was also confirmed (P0.05); the targetscan software predicted that the target gene of microRNA-99b was m TOR. luciferase reporter gene experiment confirmed that microRNA-99b was able to combine with the 3 '-UTR of M TOR; Western blot results showed that microRNA-99b by inhibiting the expression of protein to promote autophagy. Relevant data, we propose the following conclusions: 1. screening and identification of the differential expression of long chain noncoding RNA caused by H.pylori infection, and found that XLOC_004122 and XLOC_014388 are significantly different in the tissue samples of the clinical H.pylori infection, and have a linear correlation with the intestinal metaplasia. These results suggest that these two segments are in clinical treatment and prognosis. The possible sign of the function.2. found that microRNA-146a regulates cell apoptosis and canceration in H.pylori infection, and confirms that the function of.MicroRNA-146a is also positively related to the lymphatic metastasis of gastric cancer by targeting COX-2, and it is found that microRNA-99b stimulates cell autophagy in H.pylori infection and thus up-regulates the cell bactericidal ability. The function is achieved by inhibiting the function of M TOR protein.
【學(xué)位授予單位】：大連醫(yī)科大學(xué)
【學(xué)位級(jí)別】：博士
【學(xué)位授予年份】：2016
【分類號(hào)】：R378

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