本文選題：潰瘍性結(jié)腸炎 + 活動(dòng)度評(píng)估��； 參考：《北京協(xié)和醫(yī)學(xué)院》2017年博士論文

【摘要】：研究背景和目的潰瘍性結(jié)腸炎相關(guān)結(jié)直腸癌(ulcerative colitis related colorectal cancer,UCRCC)是潰瘍性結(jié)腸炎(ulcerative colitis,UC)主要的并發(fā)癥之一。目前UC活動(dòng)度評(píng)估和癌變監(jiān)測(cè)缺乏理想的血清標(biāo)志物。本研究擬在UC患者和小鼠模型中探索MicroRNA(miRNA)和長(zhǎng)鏈非編碼 RNA(long non-coding RNA,lncRNA)在 UC 活動(dòng)度評(píng)估和癌變監(jiān)測(cè)中的應(yīng)用并初步探究其作用機(jī)制。第一部分UC活動(dòng)度和癌變監(jiān)測(cè)相關(guān)血清非編碼RNA初探方法:1.應(yīng)用qRT-PCR技術(shù),在對(duì)照組(n=35)、輕度UC組(n=21)和重度UC組(n=33)血清中對(duì) 5 種候選非編碼 RNA(miR-223、miR-21、miR-126、GAS5和SLC25A25-AS1)進(jìn)行篩選,用ROC曲線分析非編碼RNA對(duì)UC疾病活動(dòng)度的評(píng)估效力,并將非編碼RNA表達(dá)情況與血沉ESR、超敏C反應(yīng)蛋白hsCRP和內(nèi)鏡下Mayo評(píng)分進(jìn)行相關(guān)性分析。2.在對(duì)照組(n=35)和結(jié)直腸癌組(n=30)血清中檢測(cè)候選miRNAs表達(dá)情況。結(jié)果:1.UC疾病活動(dòng)度相關(guān):miR-223在重度UC組較輕度UC組和對(duì)照組高表達(dá),分別為 2.40 倍(P=0.0018)和 6.97 倍(P0.0001);miR-223 在輕度 UC 組較對(duì)照組高表達(dá),為2.90倍(P=0.0024)。GAS5在重度UC組較輕度UC組和對(duì)照組低表達(dá),分別為 0.812 倍(P=0.0063)和 0.793 倍(P=0.0197)。聯(lián)合 miR-223 和 GAS5區(qū)分輕度和重度UC的敏感性和特異性可達(dá)75.8%和85.7%。miR-223的表達(dá)與ESR、hsCRP、內(nèi)鏡下Mayo評(píng)分呈正相關(guān)(P0.05);GAS5的表達(dá)與hsCRP和內(nèi)鏡下Mayo評(píng)分呈負(fù)相關(guān)(P0.05);miR-223的表達(dá)與改良Mayo評(píng)分的Spearman相關(guān)系數(shù)高于ESR和hsCRP,稍低于內(nèi)鏡下Mayo評(píng)分。2.UC癌變監(jiān)測(cè)相關(guān):miR-21在結(jié)直腸癌組較對(duì)照組、輕度UC組和重度UC組均高表達(dá),分別為 2.42 倍(P=0.0030)、5.66 倍(P0.0001)和 2.40 倍(P0.0001)。結(jié)論:1.miR-223和GAS5的血清表達(dá)水平與UC疾病活動(dòng)度相關(guān)。2.miR-223與GAS5對(duì)UC活動(dòng)度的聯(lián)合評(píng)估效力具有較高的敏感性和特異性,提示兩者聯(lián)合使用是潛在的評(píng)估UC活動(dòng)度的血清學(xué)指標(biāo)。3.miR-223和GAS5的表達(dá)與臨床常用于評(píng)估UC活動(dòng)度的指標(biāo)具有相關(guān)性,且miR-223表達(dá)與改良Mayo評(píng)分的相關(guān)性優(yōu)于ESR和hsCRP。4.miR-21有可能作為結(jié)直腸癌監(jiān)測(cè)的候選血清標(biāo)志物。第二部分非編碼RNA在小鼠模型和UC患者腸組織的表達(dá)和機(jī)制初探方法:應(yīng)用qRT-PCR技術(shù),在模型小鼠(結(jié)腸炎模型和炎癌模型)和UC患者各組腸組織中檢測(cè)候選非編碼RNA以及miR-223靶mRNA和相關(guān)炎癥因子mRNA的表達(dá)情況。結(jié)腸炎模型組小鼠設(shè)DSS7組、DSS9組和DSS12組,分別在給予DSS后第7、9、12天處死。結(jié)果:1.結(jié)腸炎模型小鼠腸道炎癥程度:DSS7組DSS9組DSS12組。2.非編碼RNA:miR-223、miR-21和miR-126在DSS7組較對(duì)照組、DSS9組和DSS12組顯著高表達(dá);GAS5在DSS7組較對(duì)照組、DSS9組和DSS12組顯著低表達(dá)(P值均0.05)。miR-223在炎癌模型組小鼠較對(duì)照組高表達(dá)(P=0.0420)。miR-223和miR-21在重度UC組較輕度UC和對(duì)照組顯著高表達(dá);GAS5和SLC25A25-AS1在重度UC組較輕度UC和對(duì)照組顯著低表達(dá)(P值均0.05)。3.相關(guān)mRNA:(1)靶mRNA-CLDN8表達(dá)情況:DSS7組顯著低于對(duì)照組、DSS9組和DSS12組(P值均0.05);炎癌模型組小鼠顯著低于對(duì)照組(P=0.0259);重度UC患者組顯著低于輕度UC組和對(duì)照組(P值均0.05)。(2)靶mRNA-RhoB表達(dá)情況:DSS7組低于對(duì)照組、DSS9組和DSS12組(分別為P=0.0019、P=0.0846、P0.0001);炎癌模型組小鼠稍低于對(duì)照組,無(wú)統(tǒng)計(jì)學(xué)意義;UC患者腸道中表達(dá)無(wú)明顯規(guī)律。(3)IL-1β mRNA表達(dá)情況:DSS7組顯著高于對(duì)照組、DSS9組和DSS12組(P值均0.05);炎癌模型組小鼠顯著高于對(duì)照組(P=0.0097)。重度UC患者組表達(dá)顯著高于輕度UC組和對(duì)照組(P值均0.05)。(4)IL-6 mRNA表達(dá)情況:DSS7組高于對(duì)照組、DSS9組和DSS12組(P值分別為P=0.0142、P=0.1209、P=0.1987);炎癌模型組小鼠顯著高于對(duì)照組(P=0.0341);重度UC患者組表達(dá)顯著高于輕度UC組和對(duì)照組(P值均0.05)。(5)TNF-α mRNA表達(dá)情況:DSS7組高于對(duì)照組、DSS9組和DSS12組(P值分別為P=0.0095、P=0.0998、P=0.4081);炎癌組小鼠顯著高于對(duì)照組(P=0.0148)。重度UC患者組表達(dá)高于輕度UC組和對(duì)照組(分別為P=0.3148和P=0.0289)。結(jié)論:1.miR-223、miR-21和GAS5在結(jié)腸炎模型小鼠和UC患者腸組織表達(dá)水平與炎癥程度相關(guān),且miR-223和GAS5與UC患者血清中變化趨勢(shì)一致。2.miR-126在結(jié)腸炎模型小鼠腸組織表達(dá)水平與炎癥程度相關(guān),SLC25A25-AS1在UC患者腸組織表達(dá)水平與炎癥程度相關(guān)。3.結(jié)果初步提示:miR-223可通過(guò)下調(diào)CLDN8的表達(dá)以及提高IL-1β、IL-6的表達(dá)參與UC的炎癥和癌變過(guò)程。miR-223可通過(guò)下調(diào)RhoB的表達(dá)參與小鼠腸道的炎癥過(guò)程。miR-223可通過(guò)提高TNF-α的表達(dá)參與小鼠腸道的炎癥和癌變過(guò)程。
[Abstract]:Background and objective ulcerative colitis related colorectal cancer (UCRCC) is one of the major complications of ulcerative colitis (ulcerative colitis, UC). Currently, UC activity assessment and canceration monitoring lack ideal serum markers. This study is intended to explore Micro in UC and mouse models. The application of RNA (miRNA) and long chain non coded RNA (long non-coding RNA, lncRNA) in UC activity evaluation and cancer monitoring and preliminary exploration of its mechanism. The first part of part UC activity and cancer monitoring related serum non coded RNA methods: 1. using qRT-PCR technique in group (n=35), mild and severe serum 5 candidate non coded RNA (miR-223, miR-21, miR-126, GAS5 and SLC25A25-AS1) were screened and the ROC curve was used to analyze the effectiveness of non coded RNA on the degree of UC disease activity. The correlation analysis of non coded RNA expression with the ESR, hypersensitive C reactive protein and the colorectal cancer was carried out in the control group and the colorectal cancer. The expression of candidate miRNAs in the serum of cancer group (n=30) was detected. Results: the degree of activity of 1.UC disease was associated with the higher expression of miR-223 in the severe UC group than in the mild UC group and the control group, 2.40 times (P=0.0018) and 6.97 times (P0.0001), respectively, and the miR-223 in the mild UC group was higher than the control group, and 2.90 times (P=0.0024).GAS5 in the severe group than the mild group and the opposite group. The low expression in the group was 0.812 times (P=0.0063) and 0.793 times (P=0.0197). The sensitivity and specificity of combination of miR-223 and GAS5 for mild and severe UC and the expression of 85.7%.miR-223 were positively correlated with ESR, hsCRP, and endoscopic Mayo score (P0.05); GAS5 expression was negatively correlated with hsCRP and endoscopy. The Spearman correlation coefficient of the modified Mayo score was higher than that of ESR and hsCRP, which was slightly lower than the monitoring of.2.UC carcinogenesis under the endoscopic Mayo score: miR-21 was higher in the colorectal cancer group than in the control group, in the mild UC group and in the severe UC group, respectively, 2.42 times (P=0.0030), 5.66 times (P0.0001) and 2.40 times (P0.0001). The levels of.2.miR-223 and GAS5 are highly sensitive and specific to the combined evaluation of UC activity in relation to the degree of activity of UC, suggesting that the combination of the two is a potential serological indicator of the degree of activity of UC, the expression of.3.miR-223 and GAS5, which is associated with the clinical evaluation of UC activity, and the expression of miR-223 The correlation of the improved Mayo score is superior to that of ESR and hsCRP.4.miR-21 as a candidate serum marker for colorectal cancer monitoring. The expression and mechanism of the second part of the non coded RNA in the mouse model and the intestinal tissue of the UC patients: the use of qRT-PCR technology in the model mice (colitis model and inflammatory cancer model) and the intestinal tissues of the UC patients. The expression of candidate non coding RNA, miR-223 target mRNA and related inflammatory factor mRNA were detected. The mice in the colitis model group were set up in DSS7 group, DSS9 group and DSS12 group, and were executed on day 7,9,12 after DSS, respectively. Results: the degree of intestinal inflammation in 1. colitis model mice: DSS7 group DSS9 group DSS12 group Compared with control group, group DSS9 and group DSS12 were highly expressed in group DSS9 and group DSS12, and in group DSS7, the expression of.MiR-223 in DSS9 group and DSS12 group (P value) was higher than that in control group (P=0.0420) in the model group of inflammatory cancer (P=0.0420) and miR-21 in severe UC group and control group. UC and control group were significantly lower expression (P 0.05).3. related mRNA: (1) target mRNA-CLDN8 expression: DSS7 group was significantly lower than the control group, DSS9 group and DSS12 group (P value was 0.05), and the model group of inflammatory cancer was significantly lower than the control group (P=0.0259), and the severe UC patient group was significantly lower than the light intensity UC group and the control group (0.05). (2) the target expression situation: 2 The group was lower than the control group, DSS9 group and DSS12 group (P=0.0019, P=0.0846, P0.0001), and the mice in the model group were slightly lower than the control group. There was no significant difference in the intestinal expression in the UC patients. (3) the expression of IL-1 beta mRNA was significantly higher than the control group, the DSS9 group and DSS12 group (P values were 0.05), and the mice in the model group of inflammatory cancer were significantly higher than the control group. Group (P=0.0097). The expression of severe UC patients was significantly higher than that in the mild UC group and the control group (P value was 0.05). (4) the expression of IL-6 mRNA: the DSS7 group was higher than the control group, DSS9 and DSS12 group (P value was P=0.0142, P=0.1209,), and the expression of the severe patients was significantly higher than that of the mild group and the control group. (P 0.05). (5) the expression of TNF- alpha mRNA: the DSS7 group was higher than the control group, DSS9 group and DSS12 group (P value was P=0.0095, P=0.0998, P=0.4081), and the mice in the inflammatory cancer group were significantly higher than the control group (P=0.0148). The expression level of intestinal tissue in the inflammatory model mice and the UC patients was related to the degree of inflammation, and the changes in the serum of miR-223 and GAS5 were in accordance with the changes in the serum of UC patients. The expression level of intestinal tissue in the colitis model mice was related to the degree of inflammation. The.3. results associated with the expression level of SLC25A25-AS1 in the intestinal tissue of the UC patients and the degree of inflammation were preliminarily suggested: miR-223 can be found. The expression of CLDN8 and the expression of IL-1 beta and IL-6 are involved in the inflammation and carcinogenesis of UC..miR-223 can participate in the inflammatory process of intestinal tract by decreasing the expression of RhoB, and.MiR-223 can be involved in the inflammation and carcinogenesis of the intestinal tract in mice by increasing the expression of TNF- a.
【學(xué)位授予單位】：北京協(xié)和醫(yī)學(xué)院
【學(xué)位級(jí)別】：博士
【學(xué)位授予年份】：2017
【分類號(hào)】：R574.62

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