Alteration of metabolic conditions impacts the regulation of IGF-II/H19 imprinting status in prostate cancer

Kingshott, Georgina, Biernacka, Kalina, Sewell, Alex, Gwiti, Paida, Barker, Rachel, Zielinska, Hanna, Gilkes, Amanda, McCarthy, Kathryn, Martin, Richard M., Lane, J. Athene, McGeagh, Lucy, Koupparis, Anthony, Rowe, Edward, Oxley, Jon, Holly, Jeff M. P. and Perks, Claire M. 2021. Alteration of metabolic conditions impacts the regulation of IGF-II/H19 imprinting status in prostate cancer. Cancers 13 (4) , 825. 10.3390/cancers13040825

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Abstract

Prostate cancer is the second major cause of male cancer deaths. Obesity, type 2 diabetes, and cancer risk are linked. Insulin-like growth factor II (IGF-II) is involved in numerous cellular events, including proliferation and survival. The IGF-II gene shares its locus with the lncRNA, H19. IGF-II/H19 was the first gene to be identified as being “imprinted”—where the paternal copy is not transcribed—a silencing phenomenon lost in many cancer types. We disrupted imprinting behaviour in vitro by altering metabolic conditions and quantified it using RFLP, qPCR and pyrosequencing; changes to peptide were measured using RIA. Prostate tissue samples were analysed using ddPCR, pyrosequencing and IHC. We compared with in silico data, provided by TGCA on the cBIO Portal. We observed disruption of imprinting behaviour, in vitro, with a significant increase in IGF-II and a reciprocal decrease in H19 mRNA; the increased mRNA was not translated into peptides. In vivo, most specimens retained imprinting status apart from a small subset which showed reduced imprinting. A positive correlation was seen between IGF-II and H19 mRNA expression, which concurred with findings of larger Cancer Genome Atlas (TGCA) cohorts. This positive correlation did not affect IGF-II peptide. Our findings show that type 2 diabetes and/or obesity, can directly affect regulation growth factors involved in carcinogenesis, indirectly suggesting a modification of lifestyle habits may reduce cancer risk.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Medicine
Additional Information:	This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/
Publisher:	MDPI
ISSN:	2072-6694
Date of First Compliant Deposit:	26 August 2021
Date of Acceptance:	9 February 2021
Last Modified:	23 May 2023 14:22
URI:	https://orca.cardiff.ac.uk/id/eprint/143698

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