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Expression profile of intestinal stem cell markers in colitis-associated carcinogenesis.

ABSTRACT: The intestinal epithelium has two distinct two stem cell populations, namely, crypt base columnar (CBC) cells and +4 cells. Several specific markers have been identified for each stem cell population. In this study, we examined the expression profiles of these markers in colitis-associated carcinogenesis (CAC) to investigate whether they can be used as biomarkers for the early detection of dysplasia. The expression of intestinal stem cell (ISC) markers was measured by real-time polymerase chain reaction during CAC that was induced by azoxymethane and dextran sodium sulfate treatment. CBC stem cell markers increased continuously with tumor development, whereas a +4 cell expression profile was not present. CBC stem cell population was suppressed in the acute colitis and then expanded to repopulate the crypts during the regeneration period. Notably, RNA in situ hybridization revealed that all dysplasia and cancer samples showed increased expression of CBC stem cell markers in more than one-third of the tumor height, whereas regenerative glands had CBC stem cell markers confined to the lower one-third of the crypt. These results suggest that CBC stem cell markers could be a useful tool for the early detection of colitis-induced tumors.

SUBMITTER: Kim HS

PROVIDER: S-EPMC5529509 | biostudies-literature | 2017 Jul

REPOSITORIES: biostudies-literature

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Expression profile of intestinal stem cell markers in colitis-associated carcinogenesis.

Kim Hye Sung HS Lee Cheol C Kim Woo Ho WH Maeng Young Hee YH Jang Bo Gun BG

Scientific reports 20170726 1

The intestinal epithelium has two distinct two stem cell populations, namely, crypt base columnar (CBC) cells and +4 cells. Several specific markers have been identified for each stem cell population. In this study, we examined the expression profiles of these markers in colitis-associated carcinogenesis (CAC) to investigate whether they can be used as biomarkers for the early detection of dysplasia. The expression of intestinal stem cell (ISC) markers was measured by real-time polymerase chain ...[more]

PMID: 28747693

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Project description:Intestinal epithelial barrier protects intestine from infection and injury, while chronic inflammation is a trigger for tumorigenesis. As a member of tight junctions (TJs) family, Claudin-7 (Cldn-7) is dedicated to maintaining cell polarity and TJs barrier integrity, and closely related to the development of inflammation and tumors. However, potential roles of Cldn-7 in intestinal inflammation and colitis-associated colorectal cancer (CAC) have not been well characterized in vivo. Here, we analyzed the expression profile of Cldn-7 in inflammatory bowel disease (IBD) and CAC. Colitis and colitis-cancer transformation models were established based on inducible intestinal conditional Cldn-7 gene knockout mice (Cldn7fl/fl;villin-CreERT2), by intraperitoneal injection of azomethane (AOM) and dextran sodium sulfate (DSS) feeding. Cldn-7 knockout promoted susceptibility to colitis and CAC, aggravated clinical symptoms, severely damaged intestinal epithelium, increased mucosal inflammation accompanied dysregulated cell proliferation-apoptosis. Epithelial barrier integrity was destroyed, and intercellular permeability was increased. After AOM/DSS induction, tumor burden and volume were increased, characterized by enhanced proliferation and activation of Wnt/β-catenin signaling pathway. Mechanistically, Cldn-7 deficiency promoted colitis and subsequently malignant transformation by destroying TJs integrity and increasing inflammatory cascade. Overall, based on Cldn-7 knockout mouse model, we have first demonstrated the key roles of Cldn-7 in maintaining intestinal homeostasis and preventing IBD and consequent CAC. Abbreviations: AJs: adherens junctions; AOM: azomethane; Cldn-7: Claudin-7; CRC: colorectal cancer; CAC: colitis-associated colorectal cancer; CD: Crohn's disease; DSS: dextran sodium sulfate; DAI: disease activity index; EMT: epithelial-mesenchymal transition; FITC: fluorescence isothiocyanate; HB: hemoglobin; IBD: inflammatory bowel disease; IECs: intestinal epithelial cells; ISCs: intestinal stem cells; PLT: platelet; RBC: red blood cell; ROS: reactive oxygen species; TAM: tamoxifen; TJs: tight junctions; TCF/LEF: T-cell factor/lymphoid enhancer factor; UC: ulcerative colitis; WBC: white blood cell.

Project description:BackgroundLongstanding 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.MethodsTwo 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.ResultsmiR-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.ConclusionsWe 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.

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Expression profile of intestinal stem cell markers in colitis-associated carcinogenesis.

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Expression profile of intestinal stem cell markers in colitis-associated carcinogenesis.

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