Orchestration of miRNA patterns by testosterone and dietary tomato carotenoids during early prostate carcinogenesis in TRAMP mice

Authors: WAN, LEI - The Ohio State University; THOMAS-AHNER, JENNIFER - The Ohio State University; PEARL, DENNIS - Pennsylvania State University; ERDMAN, JOHN - University Of Illinois; MORAN, NANCY - Children'S Nutrition Research Center (CNRC); CLINTON, STEVEN - The Ohio State University

Submitted to: Journal of Nutrition
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 5/11/2023
Publication Date: 5/13/2023
Citation: Wan, L., Thomas-Ahner, J.M., Pearl, D.K., Erdman, J.W., Moran, N.E., Clinton, S.K. 2023. Orchestration of miRNA patterns by testosterone and dietary tomato carotenoids during early prostate carcinogenesis in TRAMP mice. Journal of Nutrition. 153(7):1877-1888. https://doi.org/10.1016/j.tjnut.2023.05.015.
DOI: https://doi.org/10.1016/j.tjnut.2023.05.015

Interpretive Summary: Prostate cancer risk is influence by genetic damage, diet, and hormones. MicroRNAs (miRNAs) are small pieces of genetic material that can also modulate cancer risk. Whether diet and hormones change miRNA profiles during early prostate cancer development is unknown. In this study, mice with or without a genetic risk to develop prostate cancer were fed either cancer prevention diets containing tomato or lycopene, or control diets and either had their usual hormone status, reduced testosterone, or reduced then replaced testosterone. The miRNA profiles in the mouse prostates differed most greatly between the mice with or without the genetic risk factor to develop prostate cancer. Those cancer-sensitive miRNAs were also sensitive to testosterone and diet type. The cancer protective lycopene and tomato diets led to changes in miRNAs related to known cancer-related pathways. These results suggest that cancer preventive foods containing tomato or lycopene may affect cancer risk by changing miRNA expression profiles.

Technical Abstract: The integrative impacts of prostate cancer risk factors, such as diet and endocrine status, on cancer-associated miRNA expression are poorly defined. This study defines the influence of androgens and diet (tomato and lycopene) on prostatic miRNA expression during early carcinogenesis in the transgenic adenocarcinoma of the mouse prostate (TRAMP) model. Wild type (WT) and TRAMP mice were fed control, tomato-, or lycopene-containing diets from 4-10 weeks-of-age. Mice underwent either sham (intact) or castration surgery at 8 weeks, and half of the castrated mice received testosterone (2.5 mg/kg body weight/d) at 9 weeks. Mice were terminated at 10 weeks, and dorsolateral prostate expression of 602 miRNAs was assessed. We detected expression of 88 miRNAs (15% of 602), all of which were present in the TRAMP, in comparison to 49 miRNAs being detectable (8%) in WT. Expression of 61 miRNAs differed by TRAMP genotype, with the majority upregulated in TRAMP. Of the 61 miRNAs, 42 were responsive to androgen status. Diet impacted 41% of the miRNAs, which differed by genotype (25/61), and 48% of the androgen-sensitive miRNAs (20/42), indicating overlapping genetic and dietary influences on prostate miRNAs. Tomato and lycopene-feeding influenced miRNAs previously associated with the regulation of androgen-(miR-145 and let-7), MAPK (Mitogen-Activated Protein Kinase 1)-(miR-106a, 204, 145/143 and 200b/c) and p53-signaling (miR-125 and miR-98) pathways. Expression of miRNAs in early prostate carcinogenesis is sensitive to genetic, endocrine, and diet drivers, suggesting novel mechanisms by which tomato and lycopene feeding modulate early prostate carcinogenesis.