Colonic Mucosal Transcriptomic Changes in Patients with Long-Duration Ulcerative Colitis Revealed Colitis-Associated Cancer Pathways

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Abstract

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.

Original languageEnglish
Pages (from-to)755-763
Number of pages9
JournalJournal of Crohn's & colitis
Volume13
Issue number6
DOIs
Publication statusPublished - 27 May 2019

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Colitis
Ulcerative Colitis
Neoplasms
Alternative Splicing
Genes
Gene Expression Profiling
Gene Expression
Peroxisome Proliferator-Activated Receptors
Isoleucine
Valine
Microarray Analysis
Metabolic Networks and Pathways
Transcriptome
Bile
Leucine
Protein Isoforms
Fatty Acids
Down-Regulation
Biopsy

Keywords

  • Inflammatory bowel disease
  • long duration
  • microarray analysis
  • transcriptome
  • ulcerative colitis

ASJC Scopus subject areas

  • Gastroenterology

Cite this

@article{fb77d7f1cf404cc79097e690ff2021be,
title = "Colonic Mucosal Transcriptomic Changes in Patients with Long-Duration Ulcerative Colitis Revealed Colitis-Associated Cancer Pathways",
abstract = "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.",
keywords = "Inflammatory bowel disease, long duration, microarray analysis, transcriptome, ulcerative colitis",
author = "Low, {Eden Ngah Den} and {Mohd Mokhtar}, Norfilza and Zhiqin Wong and {Raja Ali}, {Raja Affendi}",
year = "2019",
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language = "English",
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journal = "Journal of Crohn's and Colitis",
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T1 - Colonic Mucosal Transcriptomic Changes in Patients with Long-Duration Ulcerative Colitis Revealed Colitis-Associated Cancer Pathways

AU - Low, Eden Ngah Den

AU - Mohd Mokhtar, Norfilza

AU - Wong, Zhiqin

AU - Raja Ali, Raja Affendi

PY - 2019/5/27

Y1 - 2019/5/27

N2 - 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.

AB - 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.

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KW - microarray analysis

KW - transcriptome

KW - ulcerative colitis

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