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) |
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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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