Possible Molecular Mechanisms by which Vitamin D Prevents Inflammatory Bowel Disease and Colitis-associated Colorectal Cancer

2017 ◽  
Vol 24 (9) ◽  
pp. 911-917 ◽  
Author(s):  
Zijian Luan ◽  
Yiming Ma ◽  
Yu Xin ◽  
Jiaming Qian ◽  
Hongying Wang
Keyword(s):  
Colorectal Cancer ◽  
Inflammatory Bowel Disease ◽  
Vitamin D ◽  
Bowel Disease ◽  
Molecular Mechanisms ◽  
Inflammatory Bowel

Bringing to Light the Risk of Colorectal Cancer in Inflammatory Bowel Disease: Mucosal Glycosylation as a Key Player

2021 ◽  
Author(s):  
Eduarda Leite-Gomes ◽  
Ana M Dias ◽  
Catarina M Azevedo ◽  
Beatriz Santos-Pereira ◽  
Mariana Magalhães ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Inflammatory Bowel Disease ◽  
Bowel Disease ◽  
Molecular Mechanisms ◽  
Intestinal Inflammation ◽  
Serum Proteins ◽  
Major Complication ◽  
Cancer Pathogenesis ◽  
Colon Inflammation ◽  
Inflammatory Bowel

Abstract Colitis-associated cancer is a major complication of inflammatory bowel disease remaining an important clinical challenge in terms of diagnosis, screening, and prognosis. Inflammation is a driving factor both in inflammatory bowel disease and cancer, but the mechanism underlying the transition from colon inflammation to cancer remains to be defined. Dysregulation of mucosal glycosylation has been described as a key regulatory mechanism associated both with colon inflammation and colorectal cancer development. In this review, we discuss the major molecular mechanisms of colitis-associated cancer pathogenesis, highlighting the role of glycans expressed at gut epithelial cells, at lamina propria T cells, and in serum proteins in the regulation of intestinal inflammation and its progression to colon cancer, further discussing its potential clinical and therapeutic applications.

New developments in oestrogen signalling in colonic epithelium

2006 ◽  
Vol 34 (6) ◽  
pp. 1114-1116 ◽  
Author(s):  
O. Wada-Hiraike ◽  
M. Warner ◽  
J.-Å. Gustafsson
Keyword(s):  
Colorectal Cancer ◽  
Inflammatory Bowel Disease ◽  
Animal Models ◽  
Bowel Disease ◽  
Molecular Mechanisms ◽  
Adherens Junction ◽  
Colonic Epithelium ◽  
Proliferating Cells ◽  
Junction Protein ◽  
Inflammatory Bowel

Epidemiological studies show that oestrogen reduces the risk of colorectal cancer in postmenopausal women and ERβ (oestrogen receptor β)-selective ligands have been reported to be very effective treatment in animal models of inflammatory bowel disease. Several studies have shown that ERβ is the predominant ER in the colonic epithelium, but it is not clear whether the benefit of ERβ agonists in inflammatory bowel disease are due to their action on the colon epithelium itself, or on the immune system. In order to address this issue, we have compared colons of ERβ−/− and wild-type mice with regard to morphology, histology, proliferation and differentiation. We found that the number of proliferating cells was higher in ERβ−/− mice, and the migration of labelled cells from base to lumen of the crypts was faster. Additionally, immunohistochemical staining revealed fewer apoptotic cells (cleaved caspase 3-positive), a significant decrease in expression of the epithelial differentiation marker, cytokeratin CK20, the adherens junction protein, α-catenin, and the hemidesmosomal protein, plectin, in ERβ−/− mice. These findings suggest a role for ERβ in growth, organization and maintenance of the normal colonic crypt–villus architecture. The next step is to elucidate the molecular mechanisms that underlie the signalling of ERβ in normal cell growth and assess whether or not ERβ agonists will be useful drugs in the prevention or treatment of colorectal cancer. Dietary phyto-oestrogens are believed to play a role in protection against colorectal cancer. Lignans, such as enterolactone, an ER agonist, prevent cancer development in animal models. Since ERβ is the only ER in the colon, there is enough reason to speculate that phyto-oestrogens are acting through ERβ.

scholarly journals Vitamin D and gastrointestinal diseases: inflammatory bowel disease and colorectal cancer

2010 ◽  
Vol 4 (1) ◽  
pp. 49-62 ◽  
Author(s):  
Maitreyi Raman ◽  
Andrew N. Milestone ◽  
Julian R.F. Walters ◽  
Ailsa L. Hart ◽  
Subrata Ghosh
Keyword(s):  
Colorectal Cancer ◽  
Inflammatory Bowel Disease ◽  
Vitamin D ◽  
Bowel Disease ◽  
Gastrointestinal Diseases ◽  
Inflammatory Bowel

scholarly journals RNF20 and RNF40 regulate vitamin D receptor-dependent signaling in inflammatory bowel disease

2021 ◽  
Author(s):  
Robyn Laura Kosinsky ◽  
Maria Zerche ◽  
Ana Patricia Kutschat ◽  
Asha Nair ◽  
Zhenqing Ye ◽  
...  
Keyword(s):  
Inflammatory Bowel Disease ◽  
Vitamin D ◽  
Vitamin D Receptor ◽  
Bowel Disease ◽  
Molecular Mechanisms ◽  
Target Genes ◽  
Intestinal Inflammation ◽  
Intestinal Epithelial ◽  
Mouse Intestine ◽  
Inflammatory Bowel

AbstractDespite the identification of several genetic factors linked to increased susceptibility to inflammatory bowel disease (IBD), underlying molecular mechanisms remain to be elucidated in detail. The ubiquitin ligases RNF20 and RNF40 mediate the monoubiquitination of histone H2B at lysine 120 (H2Bub1) and were shown to play context-dependent roles in the development of inflammation. Here, we aimed to examine the function of the RNF20/RNF40/H2Bub1 axis in intestinal inflammation in IBD patients and mouse models. For this purpose, intestinal sections from IBD patients were immunohistochemically stained for H2Bub1. Rnf20 or Rnf40 were conditionally deleted in the mouse intestine and mice were monitored for inflammation-associated symptoms. Using mRNA-seq and chromatin immunoprecipitation (ChIP)-seq, we analyzed underlying molecular pathways in primary intestinal epithelial cells (IECs) isolated from these animals and confirmed these findings in IBD resection specimens using ChIP-seq.The majority (80%) of IBD patients displayed a loss of H2Bub1 levels in inflamed areas and the intestine-specific deletion of Rnf20 or Rnf40 resulted in spontaneous colorectal inflammation in mice. Consistently, deletion of Rnf20 or Rnf40 promoted IBD-associated gene expression programs, including deregulation of various IBD risk genes in these animals. Further analysis of murine IECs revealed that H3K4me3 occupancy and transcription of the Vitamin D Receptor (Vdr) gene and VDR target genes is RNF20/40-dependent. Finally, these effects were confirmed in a subgroup of Crohn’s disease patients which displayed epigenetic and expression changes in RNF20/40-dependent gene signatures. Our findings reveal that loss of H2B monoubiquitination promotes intestinal inflammation via decreased VDR activity thereby identifying RNF20 and RNF40 as critical regulators of IBD.

37 Monitoring the evolution of inflammatory bowel disease (IBD) in pediatric and adult cohorts of patients to identify biomarkers to predict cancer risk

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A38-A38
Author(s):  
Shilpa Ravindran ◽  
Heba Sidahmed ◽  
Harshitha Manjunath ◽  
Rebecca Mathew ◽  
Tanwir Habib ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Gene Expression ◽  
Colorectal Cancer ◽  
Inflammatory Bowel Disease ◽  
Bowel Disease ◽  
Mesenchymal Transition ◽  
Increased Risk ◽  
Hamad Medical Corporation ◽  
Inflammatory Bowel ◽  
Left And Right

BackgroundPatients with inflammatory bowel disease (IBD) have increased risk of developing colorectal cancer (CRC), depending on the duration and severity of the disease. The evolutionary process in IBD is driven by chronic inflammation leading to epithelial-to-mesenchymal transition (EMT) events in colonic fibrotic areas. EMT plays a determinant role in tumor formation and progression, through the acquisition of ‘stemness’ properties and the generation of neoplastic cells. The aim of this study is to monitor EMT/cancer initiating tracts in IBD in association with the deep characterization of inflammation in order to assess the mechanisms of IBD severity and progression towards malignancy.Methods10 pediatric and 20 adult IBD patients, admitted at Sidra Medicine (SM) and Hamad Medical Corporation (HMC) respectively, have been enrolled in this study, from whom gut tissue biopsies (from both left and right side) were collected. Retrospectively collected tissues (N=10) from patients with malignancy and history of IBD were included in the study. DNA and RNA were extracted from fresh small size (2–4 mm in diameter) gut tissues using the BioMasher II (Kimble) and All Prep DNA/RNA kits (Qiagen). MicroRNA (miRNA; N=700) and gene expression (N=800) profiling have been performed (cCounter platform; Nanostring) as well as the methylation profiling microarray (Infinium Methylation Epic Bead Chip kit, Illumina) to interrogate up to 850,000 methylation sites across the genome.ResultsDifferential miRNA profile (N=27 miRNA; p<0.05) was found by the comparison of tissues from pediatric and adult patients. These miRNAs regulate: i. oxidative stress damage (e.g., miR 99b), ii. hypoxia induced autophagy; iii. genes associated with the susceptibility to IBD (ATG16L1, NOD2, IRGM), iv. immune responses, such as TH17 T cell subset (miR 29). N=6 miRNAs (miR135b, 10a196b, 125b, let7c, 375) linked with the regulation of Wnt/b-catenin, EM-transaction, autophagy, oxidative stress and play role also in cell proliferation and mobilization and colorectal cancer development were differentially expressed (p<0.05) in tissues from left and right sides of gut. Gene expression signature, including genes associated with inflammation, stemness and fibrosis, has also been performed for the IBD tissues mentioned above. Methylation sites at single nucleotide resolution have been analyzed.ConclusionsAlthough the results warrant further investigation, differential genomic profiling suggestive of altered pathways involved in oxidative stress, EMT, and of the possible stemness signature was found. The integration of data from multiple platforms will provide insights of the overall molecular determinants in IBD patients along with the evolution of the disease.Ethics ApprovalThis study was approved by Sidra Medicine and Hamad Medical Corporation Ethics Boards; approval number 180402817 and MRC-02-18-096, respectively.

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