The Impact of Metabolic Disturbance on Imprinting of IGF-II in Prostate and Colorectal Cancer

Abstract

The insulin-like growth factor (IGF) axis is a complex signalling system mediates the effects of nutrition on cell growth. It is composed of two ligands, IGF-I and IGF-II, tyrosine receptors and a family of six high affinity IGF binding proteins. The IGF-II gene shares its locus with a lncRNA, H19. Both genes are subject to epigenetic regulation in the form of imprinting; a mechanism by which one parental copy of the IGF-II/H19 gene is silenced. In many malignancies, this silencing is lost, but the epigenetic events leading to this loss are yet to be determined. A link exists between cancer, type 2 diabetes (T2D) and obesity (“diabesity”). This study investigated the impact of inflammatory conditions in vitro, to mimic those synonymous with “diabesity”; loss of imprinting of IGF-II/H19 was induced in prostate and colorectal cancer cell lines. Loss of imprinting, determined by pyrosequencing, disrupted IGF-II/H19 mRNA expression but had no effect on secreted IGF-II peptide levels in prostate cancer; the impacts of disrupted IGF-II/H19 mRNA expression in relation to IGF-II peptide levels in colorectal cancer cell lines is yet to be determined. These data were compared with those in vivo, using clinical cohorts of prostate and colorectal cancer tissue. In both cohorts, approximately 30% of specimens presented with loss of imprinting of IGF-II/H19, which concurred with current evidence. Loss of imprinting increased IGF-II/H19 mRNA expression, with no changes to IGF-II peptide levels in either cohort; there was a positive correlation between IGF-II and H19 mRNA expression, regardless of imprinting status; this suggests alternative mechanisms are affecting gene transcription, in addition to imprinting loss.
Data shown by this thesis has demonstrated, for the first time, how metabolic disturbance of the cellular milieu can epigenetically affect regulation of the IGF-II/H19 gene and provides an important, additional link between T2D, obesity and cancer.

Date of Award	2 Dec 2021
Original language	English
Awarding Institution	University of Bristol
Supervisor	Kalina Biernacka (Supervisor), Claire M Perks (Supervisor) & Jeffrey Holly (Supervisor)