Alteration of Metabolic Conditions Impacts the Regulation of IGF-II/H19 Imprinting Status in Prostate Cancer

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.

DM and PCa risk: a mendelian randomization analysis

“…José Manuel Cózar-Olmo et al con rmed that functional type 2 diabetes (T2DM) related mutations might affect the risk of prostate cancer from the genetic level [36]. Georgina Kingshott et al also found that diabetes could directly affect the regulatory growth factors related to cancer, and changing living habits might signi cantly reduce the risk of prostate cancer and other cancers [37]. For the problem of recurrence after prostatectomy, relevant research showed that patients with diabetes had a higher risk of recurrence [38].…”

Role of IGF2 in the Study of Development and Evolution of Prostate Cancer

“…Although there are not many data in PC, there are reports about the role of IGF2 -mRNA and its peptide in PC, with a decrease of 80% in PC compared to non-neoplastic adjacent prostate ( Kingshott et al, 2021 ). There are also data, including the over-expression patterns of IMP3 (messenger RNA binding protein 3 related to IGF2 ) in PC, related to patients’ poor prognosis ( Zhang et al, 2020 ).…”

Case report: Molecular characterisation of adipose-tissue derived cells from a patient with ROHHAD syndrome

“…The 4 most significant hits from the RNA sequencing analysis were subjected to validation using real-time quantitative PCR as described previously ( 24 ). qPCR was performed using SYBR Green (Applied Biosystems) on a StepOne RealTime PCR machine (Thermo Fisher Scientific).…”