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

摘要

The effect of environmental factors in cellular processes has been an area ofudinterest for decades. Within this research field, emerging research niches appearudconcominantly with advances in molecular biology and genetics. One such field is theudone of molecular toxicology, which investigates the molecular and cellular events thatudcertain chemicals trigger. Chemicals that present genotoxic properties are of particularudinterest based on the potential contribution to the aetiology of cancer that theuddiscoveries of their effects might provide. A group of chemicals that belong to thisudcategory are heterocyclic amines, organic compounds that are formed during theudcooking of red meat from the pyrolysis of aminoacids. Research into heterocyclicudamines has created a well established description for their ability to create DNAudadducts that lead to mutations. Recent reports from our laboratory however, indicatedudthat certain heterocyclic amines, and in particular 2-amino-1-methyl-6-phenylimidazoud[4,5-b] pyridine (PhIP), present with molecular effects that are non genotoxic butudnevertheless carcinogenic and are very similar to those induce by the natural hormoneudestradiol in breast cancer cells. Based on these findings this thesis set out toudinvestigate whether these non-genotoxic effects of PhIP also extend to epigeneticudmechanisms of gene expression control, and more specifically microRNA expressionudregulation. MicroRNAs are a class of small non-coding RNA molecules that posttrasncriptionallyudregulate gene expression and are involved in an array of processudincluding carcinogenesis. Our results showed that PhIP, as well as estradiol, driveuddifferential regulation of microRNAs and that these effects are very similar amongstudthe two compounds. This deregulation of microRNAs could be an attributing factor toudthe cancer promoting characteristics of both estradiol and PhIP and they extend theudestrogenic character of this heterocyclic amine to the area of epigenetic regulation,udand microRNAs in particular.