Prostate-specific PTen deletion in mice activates inflammatory microRNA expression pathways in the epithelium early in hyperplasia development

Dart, D.A., Uysal Onganer, P. and Jiang, W.G. 2017. Prostate-specific PTen deletion in mice activates inflammatory microRNA expression pathways in the epithelium early in hyperplasia development. Oncogenesis. 14 (6), p. 400. doi:10.1038/s41389-017-0007-5

TitleProstate-specific PTen deletion in mice activates inflammatory microRNA expression pathways in the epithelium early in hyperplasia development
AuthorsDart, D.A.
Uysal Onganer, P.
Jiang, W.G.
Abstract

PTen loss is one of the most frequent events in prostate cancer both at the initiation stage and during late stage metastatic development. The mouse model of prostate-specific probasin-mediated Pten deletion leads to prostate intraepithelial neoplasia (PIN) leading to adenocarcinoma. Using this model, we analysed the miR and mRNA transcriptome profile of Pten−/− PIN versus wild type age-matched prostate tissues and analysed the effects of Pten loss on miR expression in the early neoplastic process. At the PIN stage, Pten loss significantly changed the expression of over 20 miRNAs and over 4000 genes. The observed miR expression indicated a strong immunological cohort, which is seen in many human and mouse cancers and is thought to derive from infiltrating B and T immune cells. However, upon in situ hybridisation, these immunologically related miRs did not correlate with immune cell location, and emanated from the prostate epithelium itself and not from the associated immune cells present. Growing Pten−/− prostate cells in culture showed that the overexpressed miRNAs seen in Pten−/− were directly in response to the overactive PI3 kinase pathway and were in part responsible in reducing target gene expression levels. Inhibition of PI3 kinase downstream regulators, or re-introducing wild type PtencDNA reduced miR overexpression resulting in increased miR target gene expression. MiR inhibitors also showed this pattern, and synergised with an mTORC1 inhibitor. Overall, Pten deletion in the prostate epithelium activated a cohort of inflammation-related miRs usually associated with immune responses from B and T cells. These oncomiRs may then accelerate carcinogenesis.

Article number400
JournalOncogenesis
Journal citation14 (6), p. 400
ISSN2157-9024
Year2017
PublisherNature Publishing Group
Publisher's version
Digital Object Identifier (DOI)doi:10.1038/s41389-017-0007-5
Publication dates
Published14 Dec 2017
LicenseCC BY 4.0

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