Colonic Mucosal Transcriptomic Changes in Patients with Long-Duration Ulcerative Colitis Revealed Colitis-Associated Cancer Pathways
Colonic Mucosal Transcriptomic Changes in Patients with Long-Duration Ulcerative Colitis Revealed Colitis-Associated Cancer Pathways
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DOI：
10.1093/ecco-jcc/jjz002
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发表时间：
2019-06-01
影响因子：
8
通讯作者：
Ali, Raja Affendi Raja
中科院分区：
文献类型：
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作者：
Low, Eden Ngah Den;Mokhtar, Norfilza Mohd;Ali, Raja Affendi Raja
背景和目的 与短病程 UC 患者相比，病程长的溃疡性结肠炎 [UC] 患者患结肠炎相关癌症 [CAC] 的风险更高。本研究的目的是确定与 UC 疾病持续时间相关的转录组差异。方法 我们对 32 个结肠活检组织进行了转录组分析[11 个是长期 UC，20 年；11 个是长期 UC，20 年；11 个是长期 UC，20 年。和 21 个短期 UC，5 年]使用 Affymetrix 人类转录组阵列 2.0。使用转录组分析控制台确定差异表达基因 [倍数变化 > 1.5，p < 0.05] 和选择性剪接事件 [剪接指数 > 1.5，p < 0.05]。使用KOBAS 3.0和DAVID 6.8进行KEGG和GO分析。使用 qPCR 对微阵列分析中选定的基因进行验证。结果两组之间共有 640 个差异表达基因。上调前十位的基因为HMGCS2、UGT2A3亚型、B4GALNT2、MEP1B、GUCA2B、ADH1C、OTOP2、SLC9A3和LYPD8；下调前十位的基因为PI3、DUOX2、VNN1、SLC6A14、GREM1、MMP1、CXCL1、TNIP3、TFF1和LCN2。在 123 个改变的 KEGG 通路中，最重要的是代谢通路；脂肪酸降解；缬氨酸、亮氨酸和异亮氨酸降解；过氧化物酶体增殖物激活受体信号通路；和胆汁分泌，此前人们认为这与 CAC 有关。分析表明，3560 个基因在长持续时间 UC 和短持续时间 UC 之间表现出差异性选择性剪接。其中，374个表达差异，强调了基因表达改变和选择性剪接之间的内在关系。结论与短程UC患者相比，长期UC患者的基因表达、通路和选择性剪接事件发生了改变，这些可以进一步验证，以提高我们对CAC发病机制的理解。
Background and aims Patients with ulcerative colitis [UC] with long disease duration have a higher risk of developing colitis-associated cancer [CAC] compared with patients with short-duration UC. The aim of this study was to identify transcriptomic differences associated with the duration of UC disease.Methods We conducted transcriptome profiling on 32 colonic biopsies [11 long-duration UC, 20 years; and 21 short-duration UC, 5 years] using Affymetrix Human Transcriptome Array 2.0. Differentially expressed genes [fold change > 1.5, p < 0.05] and alternative splicing events [splicing index > 1.5, p < 0.05] were determined using the Transcriptome Analysis Console. KOBAS 3.0 and DAVID 6.8 were used for KEGG and GO analysis. Selected genes from microarray analysis were validated using qPCR.Results There were 640 differentially expressed genes between both groups. The top ten upregulated genes were HMGCS2, UGT2A3 isoforms, B4GALNT2, MEP1B, GUCA2B, ADH1C, OTOP2, SLC9A3, and LYPD8; the top ten downregulated genes were PI3, DUOX2, VNN1, SLC6A14, GREM1, MMP1, CXCL1, TNIP3, TFF1, and LCN2. Among the 123 altered KEGG pathways, the most significant were metabolic pathways; fatty acid degradation; valine, leucine, and isoleucine degradation; the peroxisome proliferator-activated receptor signalling pathway; and bile secretion, which were previously linked with CAC. Analysis showed that 3560 genes exhibited differential alternative splicing between long- and short-duration UC. Among them, 374 were differentially expressed, underscoring the intrinsic relationship between altered gene expression and alternative splicing.Conclusions Long-duration UC patients have altered gene expressions, pathways, and alternative splicing events as compared with short-duration UC patients, and these could be further validated to improve our understanding of the pathogenesis of CAC.