miRNA-26b Overexpression in Ulcerative Colitis-associated Carcinogenesis.
miRNA-26b Overexpression in Ulcerative Colitis-associated Carcinogenesis.
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DOI：
10.1097/mib.0000000000000453
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发表时间：
2015-09
影响因子：
4.9
通讯作者：
Schneider-Stock R
中科院分区：
文献类型：
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作者：
Benderska N;Dittrich AL;Knaup S;Rau TT;Neufert C;Wach S;Fahlbusch FB;Rauh M;Wirtz RM;Agaimy A;Srinivasan S;Mahadevan V;Rümmele P;Rapti E;Gazouli M;Hartmann A;Schneider-Stock R
文章于2015年6月16日首次在线发布。补充数字内容可在文本中获得。长期溃疡性结肠炎（UC）具有发展为UC相关结直肠癌（UCC）的高风险。炎症微环境会影响microRNA的表达，进而调控靶基因的表达。microRNA-26b （miR-26b）被证明有助于正常组织的生长和分化。因此，我们旨在研究miR-26b在炎症相关结直肠癌发生中的影响。研究人员对两组不同的患者进行了调查。在回顾性组中，使用来自17名UC/UCC患者的38个样本的组织微阵列进行miR-26b原位杂交和定量逆转录聚合酶链反应分析。在前瞻性组中，我们分别在6例UC和15例非UC患者的25例新鲜冷冻结肠活检和相应的血清样本中研究了miR-26b的表达。在硅分析中，采用Ago2-RNA免疫沉淀、荧光素酶报告基因测定、定量逆转录聚合酶链反应检查和miR-26b模拟物过表达进行靶标验证。在UC和UCC患者的组织和血清中，miR-26b的表达随着疾病进展而上调。使用miR-26b和Ki-67表达水平，预测UCC具有很高的准确性。我们确定了4个新的miR-26b靶点（DIP1, MDM2， CREBBP, BRCA1）。其中，E3泛素连接酶DIP1的下调与死亡相关蛋白激酶沿正常粘膜- uc - ucc序列稳定密切相关。计算机功能通路分析显示，受miR-26b影响的常见细胞通路与癌症发生和胃肠道疾病的发展高度相关。我们认为miR-26b可以作为胃肠道系统炎症相关过程的生物标志物。由于miR-26b在散发性结肠癌中表达下调，它可以区分UCC和散发性癌症类型。
Article first published online 16 June 2015. Supplemental Digital Content is Available in the Text. Longstanding ulcerative colitis (UC) bears a high risk for development of UC-associated colorectal carcinoma (UCC). The inflammatory microenvironment influences microRNA expression, which in turn deregulates target gene expression. microRNA-26b (miR-26b) was shown to be instrumental in normal tissue growth and differentiation. Thus, we aimed to investigate the impact of miR-26b in inflammation-associated colorectal carcinogenesis. Two different cohorts of patients were investigated. In the retrospective group, a tissue microarray with 38 samples from 17 UC/UCC patients was used for miR-26b in situ hybridization and quantitative reverse transcription polymerase chain reaction analyses. In the prospective group, we investigated miR-26b expression in 25 fresh–frozen colon biopsies and corresponding serum samples of 6 UC and 15 non-UC patients, respectively. In silico analysis, Ago2-RNA immunoprecipitation, luciferase reporter assay, quantitative reverse transcription polymerase chain reaction examination, and miR-26b mimic overexpression were employed for target validation. miR-26b expression was shown to be upregulated with disease progression in tissues and serum of UC and UCC patients. Using miR-26b and Ki-67 expression levels, an UCC was predicted with high accuracy. We identified 4 novel miR-26b targets (DIP1, MDM2, CREBBP, BRCA1). Among them, the downregulation of the E3 ubiquitin ligase DIP1 was closely related to death-associated protein kinase stabilization along the normal mucosa-UC-UCC sequence. In silico functional pathway analysis revealed that the common cellular pathways affected by miR-26b are highly related to cancerogenesis and the development of gastrointestinal diseases. We suggest that miR-26b could serve as a biomarker for inflammation-associated processes in the gastrointestinal system. Because miR-26b expression is downregulated in sporadic colon cancer, it could discriminate between UCC and the sporadic cancer type.