Can interleukin-6 promote human colorectal cancer progression through changes in microRNA expression?
File(s)
Author(s)
Patel, Saroor Ashfaq Ahmad
Type
Thesis
Abstract
Colorectal cancer (CRC) is the third most common cancer worldwide with over a million new cases each year. Eighty percent of CRC cases have no genetic predisposition and result from a series of epigenetic and genetic alterations, referred to as ‘sporadic’ CRC. Diets rich in red or processed meats (containing dietary carcinogens) as well as bowel inflammation are a major risk factors for disease, however the underlying mechanisms are not yet well understood. Upregulation of pro-inflammatory cytokines and cytochrome P450 (CYP450) enzymes that activate dietary carcinogens as well as microRNA (miRNA) dysregulation have been observed in CRC tissue. Interleukin-6 (IL6) is a multifunctional cytokine thought to play numerous roles in tumour progression including activation of tumour-promoting signalling pathways, epigenetic gene regulation and alteration of DNA repair mechanisms; thus presence of IL6 may be key to promoting CRC tumour progression. I hypothesised that elevated levels of IL6 in the tumour microenvironment (TME) could alter miRNA expression and induce local activation of dietary carcinogens, thereby stimulating epigenetic and genetic changes that promote CRC. The current project investigated this hypothesis using a mechanistic approach with in vitro cell culture techniques. Phenotypic changes in response to IL6 treatment were observed and the underlying causes were determined by performing genetic and epigenetic studies. The findings from this project identified three potential mechanisms of IL6-mediated CRC promotion, which involve miRNAs, STAT3 signalling and DNA methylation. First, IL6 promoted dietary carcinogen-mediated DNA damage by inducing CYP450 expression. Second, IL6 stimulated CRC cell proliferation, migration and invasion through gene and miRNA expression changes. Third, IL6-
mediated CRC-immune cell crosstalk in the TME resulting in the maintenance of IL6 secretion. Taken together, these data suggest that IL6 plays multiple roles in promoting CRC. Understanding these molecular events could lead to better prevention and therapeutic strategies.
mediated CRC-immune cell crosstalk in the TME resulting in the maintenance of IL6 secretion. Taken together, these data suggest that IL6 plays multiple roles in promoting CRC. Understanding these molecular events could lead to better prevention and therapeutic strategies.
Version
Open Access
Date Issued
2015-03
Date Awarded
2015-08
Copyright Statement
Attribution NoDerivatives 4.0 International Licence (CC BY-ND)
Advisor
Gooderham, Nigel
Sponsor
Medical Research Council (Great Britain)
Publisher Department
Department of Surgery & Cancer
Publisher Institution
Imperial College London
Qualification Level
Doctoral
Qualification Name
Doctor of Philosophy (PhD)