Abstract
BackgroundPatients with ulcerative colitis (UC) are predisposed to colitis-associated colorectal cancer (CAC). However, the transcriptional mechanism of the transformation from UC to CAC is not fully understood.MethodologyFirstly, we showed that CAC and non-UC-associated CRC were very similar in gene expression. Secondly, based on multiple datasets for UC and CRC, we extracted differentially expressed (DE) genes in UC and CRC versus normal controls, respectively. Thirdly, we compared the dysregulation directions (upregulation or downregulation) between DE genes of UC and CRC in CRC-related functions overrepresented with the DE genes of CRC, and proposed a regulatory model to explain the CRC-like dysregulation of genes in UC. A case study for “positive regulation of immune system process” was done to reveal the functional implication of DE genes with reversal dysregulations in these two diseases.Principal FindingsIn all the 44 detected CRC-related functions except for “viral transcription”, the dysregulation directions of DE genes in UC were significantly similar with their counterparts in CRC, and such CRC-like dysregulation in UC could be regulated by transcription factors affected by pro-inflammatory stimuli for colitis. A small portion of genes in each CRC-related function were dysregulated in opposite directions in the two diseases. The case study showed that genes related to humoral immunity specifically expressed in B cells tended to be upregulated in UC but downregulated in CRC.ConclusionsThe CRC-like dysregulation of genes in CRC-related functions in UC patients provides hints for understanding the transcriptional basis for UC to CRC transition. A small portion of genes with distinct dysregulation directions in each of the CRC-related functions in the two diseases implicate that their reversal dysregulations might be critical for UC to CRC transition. The cases study indicates that the humoral immune response might be inhibited during the transformation from UC to CRC.
Highlights
Ulcerative colitis (UC) is a chronic inflammatory disease caused by persistent pro-inflammatory stimuli, such as microbial products and autoimmune injury [1], and patients with ulcerative colitis (UC) are at increased risk for development of colorectal cancer (CRC), referred to as colitis-associated colorectal cancer (CAC) [2]
We proposed a regulatory model to explain the CRC-like dysregulation of genes in UC, based on the assumption that the dysregulation of the genes in UC could be regulated by transcription factors (TFs) that are affected by pro-inflammatory stimuli for colitis
Similar DE Genes in UC and CRC Firstly, using the Significance Analysis of Microarrays (SAM) method with 10% false discovery rate (FDR) control, we found no genes differentially expressed between non-UC associated CRC and CAC based on the dataset GSE3629
Summary
Ulcerative colitis (UC) is a chronic inflammatory disease caused by persistent pro-inflammatory stimuli, such as microbial products and autoimmune injury [1], and patients with UC are at increased risk for development of colorectal cancer (CRC), referred to as colitis-associated colorectal cancer (CAC) [2]. Current evidence suggests that molecular alterations in patients with UC may promote neoplastic transformation by disturbing multiple cancer-related functions. It is known that the disturbance in some critical cancer-related functions occurs in opposite directions in UC and CAC. UC-associated and non-UC-associated CRC could be very similar in gene expression, as non-UC-associated CRC is somehow driven by pathways involved in inflammation [15] with similar inflammatory signature genes characteristic of CAC [16] and nonUC-associated CRC and CAC are similar in most of the essential stages of cancer development with disturbed signaling pathways [17]. The transcriptional mechanism of the transformation from UC to CAC is not fully understood
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