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非编码RNA在溃疡性结肠炎活动度评估和癌变监测的应用及机理初探

发布时间:2018-07-01 19:32

  本文选题:溃疡性结肠炎 + 活动度评估 ; 参考:《北京协和医学院》2017年博士论文


【摘要】:研究背景和目的溃疡性结肠炎相关结直肠癌(ulcerative colitis related colorectal cancer,UCRCC)是溃疡性结肠炎(ulcerative colitis,UC)主要的并发症之一。目前UC活动度评估和癌变监测缺乏理想的血清标志物。本研究拟在UC患者和小鼠模型中探索MicroRNA(miRNA)和长链非编码 RNA(long non-coding RNA,lncRNA)在 UC 活动度评估和癌变监测中的应用并初步探究其作用机制。第一部分UC活动度和癌变监测相关血清非编码RNA初探方法:1.应用qRT-PCR技术,在对照组(n=35)、轻度UC组(n=21)和重度UC组(n=33)血清中对 5 种候选非编码 RNA(miR-223、miR-21、miR-126、GAS5和SLC25A25-AS1)进行筛选,用ROC曲线分析非编码RNA对UC疾病活动度的评估效力,并将非编码RNA表达情况与血沉ESR、超敏C反应蛋白hsCRP和内镜下Mayo评分进行相关性分析。2.在对照组(n=35)和结直肠癌组(n=30)血清中检测候选miRNAs表达情况。结果:1.UC疾病活动度相关:miR-223在重度UC组较轻度UC组和对照组高表达,分别为 2.40 倍(P=0.0018)和 6.97 倍(P0.0001);miR-223 在轻度 UC 组较对照组高表达,为2.90倍(P=0.0024)。GAS5在重度UC组较轻度UC组和对照组低表达,分别为 0.812 倍(P=0.0063)和 0.793 倍(P=0.0197)。联合 miR-223 和 GAS5区分轻度和重度UC的敏感性和特异性可达75.8%和85.7%。miR-223的表达与ESR、hsCRP、内镜下Mayo评分呈正相关(P0.05);GAS5的表达与hsCRP和内镜下Mayo评分呈负相关(P0.05);miR-223的表达与改良Mayo评分的Spearman相关系数高于ESR和hsCRP,稍低于内镜下Mayo评分。2.UC癌变监测相关:miR-21在结直肠癌组较对照组、轻度UC组和重度UC组均高表达,分别为 2.42 倍(P=0.0030)、5.66 倍(P0.0001)和 2.40 倍(P0.0001)。结论:1.miR-223和GAS5的血清表达水平与UC疾病活动度相关。2.miR-223与GAS5对UC活动度的联合评估效力具有较高的敏感性和特异性,提示两者联合使用是潜在的评估UC活动度的血清学指标。3.miR-223和GAS5的表达与临床常用于评估UC活动度的指标具有相关性,且miR-223表达与改良Mayo评分的相关性优于ESR和hsCRP。4.miR-21有可能作为结直肠癌监测的候选血清标志物。第二部分非编码RNA在小鼠模型和UC患者肠组织的表达和机制初探方法:应用qRT-PCR技术,在模型小鼠(结肠炎模型和炎癌模型)和UC患者各组肠组织中检测候选非编码RNA以及miR-223靶mRNA和相关炎症因子mRNA的表达情况。结肠炎模型组小鼠设DSS7组、DSS9组和DSS12组,分别在给予DSS后第7、9、12天处死。结果:1.结肠炎模型小鼠肠道炎症程度:DSS7组DSS9组DSS12组。2.非编码RNA:miR-223、miR-21和miR-126在DSS7组较对照组、DSS9组和DSS12组显著高表达;GAS5在DSS7组较对照组、DSS9组和DSS12组显著低表达(P值均0.05)。miR-223在炎癌模型组小鼠较对照组高表达(P=0.0420)。miR-223和miR-21在重度UC组较轻度UC和对照组显著高表达;GAS5和SLC25A25-AS1在重度UC组较轻度UC和对照组显著低表达(P值均0.05)。3.相关mRNA:(1)靶mRNA-CLDN8表达情况:DSS7组显著低于对照组、DSS9组和DSS12组(P值均0.05);炎癌模型组小鼠显著低于对照组(P=0.0259);重度UC患者组显著低于轻度UC组和对照组(P值均0.05)。(2)靶mRNA-RhoB表达情况:DSS7组低于对照组、DSS9组和DSS12组(分别为P=0.0019、P=0.0846、P0.0001);炎癌模型组小鼠稍低于对照组,无统计学意义;UC患者肠道中表达无明显规律。(3)IL-1β mRNA表达情况:DSS7组显著高于对照组、DSS9组和DSS12组(P值均0.05);炎癌模型组小鼠显著高于对照组(P=0.0097)。重度UC患者组表达显著高于轻度UC组和对照组(P值均0.05)。(4)IL-6 mRNA表达情况:DSS7组高于对照组、DSS9组和DSS12组(P值分别为P=0.0142、P=0.1209、P=0.1987);炎癌模型组小鼠显著高于对照组(P=0.0341);重度UC患者组表达显著高于轻度UC组和对照组(P值均0.05)。(5)TNF-α mRNA表达情况:DSS7组高于对照组、DSS9组和DSS12组(P值分别为P=0.0095、P=0.0998、P=0.4081);炎癌组小鼠显著高于对照组(P=0.0148)。重度UC患者组表达高于轻度UC组和对照组(分别为P=0.3148和P=0.0289)。结论:1.miR-223、miR-21和GAS5在结肠炎模型小鼠和UC患者肠组织表达水平与炎症程度相关,且miR-223和GAS5与UC患者血清中变化趋势一致。2.miR-126在结肠炎模型小鼠肠组织表达水平与炎症程度相关,SLC25A25-AS1在UC患者肠组织表达水平与炎症程度相关。3.结果初步提示:miR-223可通过下调CLDN8的表达以及提高IL-1β、IL-6的表达参与UC的炎症和癌变过程。miR-223可通过下调RhoB的表达参与小鼠肠道的炎症过程。miR-223可通过提高TNF-α的表达参与小鼠肠道的炎症和癌变过程。
[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.
【学位授予单位】:北京协和医学院
【学位级别】:博士
【学位授予年份】:2017
【分类号】:R574.62

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