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    Investigating the role of miR-223 in Ulcerative colitis and Colitis-associated colorectal cancer.


    Flynn, Ciara (2024) Investigating the role of miR-223 in Ulcerative colitis and Colitis-associated colorectal cancer. PhD thesis, National University of Ireland Maynooth.

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    Abstract

    Aberrant intestinal inflammation is a pathological feature of Ulcerative colitis (UC), and plays a crucial role in the development of Colitis-associated colorectal cancer (CAC). However, the mechanisms behind the role of the myeloid immune compartment in this inflammatory process are not fully understood. miRNA-mediated gene expression regulates numerous biological processes, with altered miRNA expression identified in both UC and CAC. Despite this, the role of myeloid-specific microRNA’s in the inflammatory process that underpins the continuum from UC to tumorigenesis remains unresolved. Here, gene set enrichment analysis (GSEA) on a discovery RNA seq data set from treatmentnaïve paediatric patients with UC, revealed that there was a positively enriched signature for myeloid inflammation among patients who were non-responsive to therapeutics. Confirmatory analysis on an Irish validation cohort of treatment-naïve paediatric patients with UC showed a similar inflammatory profile in mucosal biopsies via RT-PCR. Expression of miR-223 was increased in patients with pancolitis and correlated with the expression disease relevant inflammatory gene sets including OSM, MMP3 and IL-6. An Azoxymethane-Dextran Sodium Sulfate (AOM/DSS) mouse model of CAC showed that miR-223 is critical limit myeloid-driven inflammation. In this model, miR-223-/y mice presented with significantly larger tumours and an enhanced proliferative signature. Immunoprofiling showed that miR-223-/y mice have significantly increased colonic myeloid immune infiltrate (neutrophils, monocytes and macrophage) following AOM/DSS. This was accompanied by an increased inflammatory chemokine and cytokine signature for monocytes and neutrophils. Bone marrow chimera studies demonstrated that myeloidexpressed miR-223 is responsible for the enhanced tumor proliferation and inflammatory response. RNA sequencing on chronic AOM/DSS samples identified several pathways that could be contributing to the development of CAC in miR-223-/y mice, including the IL-6-IL- 17a cytokine family/STAT3 signalling. Finally, to mechanistically understand how miR-223 regulates epithelial tumorigenesis following myeloid inflammation, Nitric oxide signalling was identified as a major pathway of interest. Pharmacologic inhibition, lentiviral gene knock down and colonic mouse organoids were utilized to understand how miR-223 regulated type II interferon-NOS signalling and its impact on epithelial stem cell function.
    Item Type: Thesis (PhD)
    Keywords: miR-223; Ulcerative colitis; Colitis-associated colorectal cancer;
    Academic Unit: Faculty of Science and Engineering > Biology
    Item ID: 19637
    Depositing User: IR eTheses
    Date Deposited: 03 Apr 2025 13:19
    URI: https://mural.maynoothuniversity.ie/id/eprint/19637
    Use Licence: This item is available under a Creative Commons Attribution Non Commercial Share Alike Licence (CC BY-NC-SA). Details of this licence are available here

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