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STAT3 MODULATION AS A PROMISING THERAPEUTIC OPTION IN A PRECLINICAL MOUSE MODEL OF ULCERATIVE COLITIS

ABSTRACT: Ulcerative colitis (UC) is a form of inflammatory bowel disease (IBD) that predisposes to colorectal cancer (CRC) and is modeled in mice by administration of dextran sodium sulfate (DSS) in drinking water. There are two isoforms of STAT3, STAT3α is pro-inflammatory and anti-apoptotic, while STAT3β has opposing effects on STAT3α. We examined the severity of DSS-induced colitis in transgenic-mice expressing only STAT3α ( / ) and in wild-type (WT) mice administered C188-9, a small molecule direct-inhibitor of STAT3. While manifestations of DSS-induced UC, such as mortality, weight-loss, rectal-bleeding, diarrhea, and colon-shortening, were exacerbated in / transgenic versus cage-control WT mice, all were prevented by C188-9 treatment of WT mice. C188-9 treatment also increased apoptosis of pathogenic CD4+T-cells, reduced colon-levels of IL17-positive cells, down-modulated mRNA-levels of STAT3-genes involved in inflammation, apoptosis-prevention, and colorectal-cancer-metastases. These are the only studies showing efficacy of Thus small-molecule targeting of STAT3 may be a useful novel approach in treating UC and preventing UC-associated colorectal-cancer. We performed genome-wide microarray expression profiling to gain greater understanding of the mechanisms involved in the protective effect of C188-9 in DSS-induced colitis, we examined mRNA levels in the colon of mice receiving DSS or plain water, without or with C188-9 treatment.

ORGANISM(S): Mus musculus

PROVIDER: GSE117355 | GEO | 2019/07/24

REPOSITORIES: GEO

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Project description:Inflammatory bowel disease is characterized by chronic relapsing idiopathic inflammation of the gastrointestinal tract and persistent inflammation. Studies focusing on the immune-regulatory function of reactive oxygen species (ROS) are still largely missing. In this study, we analyzed an ROS-deficient mouse model leading to colon adenocarcinoma. Colitis was induced with dextran sulfate sodium (DSS) supplied via the drinking water in wild-type (WT) and Ncf1-mutant (Ncf1) B10.Q mice using two different protocols, one mimicking recovery after acute colitis and another simulating chronic colitis. Disease progression was monitored by evaluation of clinical parameters, histopathological analysis, and the blood serum metabolome using 1H nuclear magnetic resonance spectroscopy. At each experimental time point, colons and spleens from some mice were removed for histopathological analysis and internal clinical parameters. Clinical scores for weight variation, stool consistency, colorectal bleeding, colon length, and spleen weight were significantly worse for Ncf1 than for WT mice. Ncf1 mice with only a 7-day exposure to DSS followed by a 14-day resting period developed colonic distal high-grade dysplasia in contrast to the low-grade dysplasia found in the colon of WT mice. After a 21-day resting period, there was still β-catenin-rich inflammatory infiltration in the Ncf1 mice together with high-grade dysplasia and invasive well-differentiated adenocarcinoma, while in the WT mice, high-grade dysplasia was prominent without malignant invasion and only low inflammation. Although exposure to DSS generated less severe histopathological changes in the WT group, the blood serum metabolome revealed an increased fatty acid content with moderate-to-strong correlations to inflammation score, weight variation, colon length, and spleen weight. Ncf1 mice also displayed a similar pattern but with lower coefficients and showed consistently lower glucose and/or higher lactate levels which correlated with inflammation score, weight variation, and spleen weight. In our novel, DSS-induced colitis animal model, the lack of an oxidative burst ROS was sufficient to develop adenocarcinoma, and display altered blood plasma metabolic and lipid profiles. Thus, oxidative burst seems to be necessary to prevent evolution toward cancer and may confer a protective role in a ROS-mediated self-control mechanism.

Project description:Nonresolving inflammation is correlated to carcinogenesis. Ulcerative colitis-associated colorectal cancer (UC-CRC), one of the typical carcinoma generated by inflammation that cannot be resolved properly, has been widely believed to involve a multistep process contains M-bM-^@M-^\inflammation-dysplasia-cancerM-bM-^@M-^] sequence. The exact molecular mechanisms underlying the step-wise development of UC-CRC is still not fully understood. Detecting the changes in gene expression profiles may help to reveal why and how does the prolonged inflammatory response lead to carcinogenesis, and to characterize potential diagnostic/prognostic markers or additional therapeutic targets for UC-CRC. There for, we performed temporal genome expression profiling analysis using the Affymetrix genome wide microarray system to identify broad scale changes in gene expression associated with the development of colitis-associated cancer, based on an AOM/DSS induced mouse model of UC-CRC. 6-week-old male ICR mice were given a single intraperitoneal injection of AOM (10mg/kg) at Day 1, followed by three cycles of DSS administration (cycle 1: 2%, Day 8~14; cycle 2: 1.5%, Day 29~33; cycle 3: 1.5%, Day 50~54) in the drinking water. Instead, control group of mice were given a single intraperitoneal injection of saline (10mg/kg) at Day 1 and distilled water drinking from the beginning to the end without DSS. Colorectal tissues were collected at days 14, 28, 42, 56 and 140 (at the end of the 2nd, 4th, 6th, 8th and 20th week) from the AOM/DSS group and at day 14 from the control group. Pathological changes of each sample were identified under microscope. Samples collected at the end of the 2nd week were inflamed mucosae, the 4th week were low grade dysplasias, the 6th week were high grade dysplasias, the 8th week were high grade dysplasias with active inflammation, the 20th week were carcinomas, and the control sample were normal mucosae. Total RNA were extracted and detected by Affymerix GeneChip Mouse Genome 430 2.0 Array.

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STAT3 MODULATION AS A PROMISING THERAPEUTIC OPTION IN A PRECLINICAL MOUSE MODEL OF ULCERATIVE COLITIS

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