Mechanistic studies on the molecular toxicology of the carcinogen PhIP : the role of microRNAs

• Main Author: Papaioannou, Michail-Dimitrios
• Other Authors: Gooderham, Nigel
• Published: Imperial College London 2016
• Subjects: 616.99
• Online Access: http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.695562

The effect of environmental factors in cellular processes has been an area of interest for decades. Within this research field, emerging research niches appear concominantly with advances in molecular biology and genetics. One such field is the one of molecular toxicology, which investigates the molecular and cellular events that certain chemicals trigger. Chemicals that present genotoxic properties are of particular interest based on the potential contribution to the aetiology of cancer that the discoveries of their effects might provide. A group of chemicals that belong to this category are heterocyclic amines, organic compounds that are formed during the cooking of red meat from the pyrolysis of aminoacids. Research into heterocyclic amines has created a well established description for their ability to create DNA adducts that lead to mutations. Recent reports from our laboratory however, indicated that certain heterocyclic amines, and in particular 2-amino-1-methyl-6-phenylimidazo [4,5-b] pyridine (PhIP), present with molecular effects that are non genotoxic but nevertheless carcinogenic and are very similar to those induce by the natural hormone estradiol in breast cancer cells. Based on these findings this thesis set out to investigate whether these non-genotoxic effects of PhIP also extend to epigenetic mechanisms of gene expression control, and more specifically microRNA expression regulation. MicroRNAs are a class of small non-coding RNA molecules that posttrasncriptionally regulate gene expression and are involved in an array of process including carcinogenesis. Our results showed that PhIP, as well as estradiol, drive differential regulation of microRNAs and that these effects are very similar amongst the two compounds. This deregulation of microRNAs could be an attributing factor to the cancer promoting characteristics of both estradiol and PhIP and they extend the estrogenic character of this heterocyclic amine to the area of epigenetic regulation, and microRNAs in particular.