A1 Refereed original research article in a scientific journal
In Vivo Expression of miR-32 Induces Proliferation in Prostate Epithelium
Authors: Latonen L, Scaravilli M, Gillen A, Hartikainen S, Zhang FP, Ruusuvuori P, Kujala P, Poutanen M, Visakorpi T
Publisher: ELSEVIER SCIENCE INC
Publication year: 2017
Journal: American Journal of Pathology
Journal name in source: AMERICAN JOURNAL OF PATHOLOGY
Journal acronym: AM J PATHOL
Volume: 187
Issue: 11
First page : 2546
Last page: 2557
Number of pages: 12
ISSN: 0002-9440
DOI: https://doi.org/10.1016/j.ajpath.2017.07.012
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.
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.
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