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Am J Pathol. 2017 Nov;187(11):2546-2557. doi: 10.1016/j.ajpath.2017.07.012. Epub 2017 Aug 19.

In Vivo Expression of miR-32 Induces Proliferation in Prostate Epithelium.

Author information

1
Prostate Cancer Research Center, Faculty of Medicine and Life Sciences and BioMediTech, University of Tampere, Tampere, Finland; Fimlab Laboratories, Tampere University Hospital, Tampere, Finland. Electronic address: leena.latonen@uta.fi.
2
Prostate Cancer Research Center, Faculty of Medicine and Life Sciences and BioMediTech, University of Tampere, Tampere, Finland; Fimlab Laboratories, Tampere University Hospital, Tampere, Finland.
3
Turku Center for Disease Modeling, Institute of Biomedicine, University of Turku, Turku, Finland.
4
Prostate Cancer Research Center, Faculty of Medicine and Life Sciences and BioMediTech, University of Tampere, Tampere, Finland; Tampere University of Technology, Pori, Finland.
5
Fimlab Laboratories, Tampere University Hospital, Tampere, Finland.
6
Turku Center for Disease Modeling, Institute of Biomedicine, University of Turku, Turku, Finland; Department of Physiology, Institute of Biomedicine, University of Turku, Turku, Finland.
7
Prostate Cancer Research Center, Faculty of Medicine and Life Sciences and BioMediTech, University of Tampere, Tampere, Finland; Fimlab Laboratories, Tampere University Hospital, Tampere, Finland. Electronic address: tapio.visakorpi@uta.fi.

Abstract

miRNAs are important regulators of gene expression and are often deregulated in cancer. We have previously shown that miR-32 is an androgen receptor-regulated miRNA overexpressed in castration-resistant prostate cancer and that miR-32 can improve prostate cancer cell growth in vitro. To assess the effects of miR-32 in vivo, we developed transgenic mice overexpressing miR-32 in the prostate. The study indicated that transgenic miR-32 expression increases replicative activity in the prostate epithelium. We further observed an aging-associated increase in the incidence of goblet cell metaplasia in the prostate epithelium. Furthermore, aged miR-32 transgenic mice exhibited metaplasia-associated prostatic intraepithelial neoplasia at a low frequency. When crossbred with mice lacking the other allele of tumor-suppressor Pten (miR-32xPten+/- mice), miR-32 expression increased both the incidence and the replicative activity of prostatic intraepithelial neoplasia lesions in the dorsal prostate. The miR-32xPten+/- mice also demonstrated increased goblet cell metaplasia compared with Pten+/- mice. By performing a microarray analysis of mouse prostate tissue to screen downstream targets and effectors of miR-32, we identified RAC2 as a potential, and clinically relevant, target of miR-32. We also demonstrate down-regulation of several interesting, potentially prostate cancer-relevant genes (Spink1, Spink5, and Casp1) by miR-32 in the prostate tissue. The results demonstrate that miR-32 increases proliferation and promotes metaplastic transformation in mouse prostate epithelium, which may promote neoplastic alterations in the prostate.

PMID:
28827140
DOI:
10.1016/j.ajpath.2017.07.012
[Indexed for MEDLINE]

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