Genistein Up-Regulates Tumor Suppressor MicroRNA-574-3p in Prostate Cancer

University of Toronto, Canada
PLoS ONE (Impact Factor: 3.23). 03/2013; 8(3):e58929. DOI: 10.1371/journal.pone.0058929
Source: PubMed


Genistein has been shown to inhibit cancers both in vitro and in vivo, by altering the expression of several microRNAs (miRNAs). In this study, we focused on tumor suppressor miRNAs regulated by genistein and investigated their function in prostate cancer (PCa) and target pathways. Using miRNA microarray analysis and real-time RT-PCR we observed that miR-574-3p was significantly up-regulated in PCa cells treated with genistein compared with vehicle control. The expression of miR-574-3p was significantly lower in PCa cell lines and clinical PCa tissues compared with normal prostate cells (RWPE-1) and adjacent normal tissues. Low expression level of miR-574-3p was correlated with advanced tumor stage and higher Gleason score in PCa specimens. Re-expression of miR-574-3p in PCa cells significantly inhibited cell proliferation, migration and invasion in vitro and in vivo. miR-574-3p restoration induced apoptosis through reducing Bcl-xL and activating caspase-9 and caspase-3. Using GeneCodis software analysis, several pathways affected by miR-574-3p were identified, such as 'Pathways in cancer', 'Jak-STAT signaling pathway', and 'Wnt signaling pathway'. Luciferase reporter assays demonstrated that miR-574-3p directly binds to the 3' UTR of several target genes (such as RAC1, EGFR and EP300) that are components of 'Pathways in cancer'. Quantitative real-time PCR and Western analysis showed that the mRNA and protein expression levels of the three target genes in PCa cells were markedly down-regulated with miR-574-3p. Loss-of-function studies demonstrated that the three target genes significantly affect cell proliferation, migration and invasion in PCa cell lines. Our results show that genistein up-regulates tumor suppressor miR-574-3p expression targeting several cell signaling pathways. These findings enhance understanding of how genistein regulates with miRNA in PCa.

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    • "Although microRNAs are also essential for normal human physiology, many microRNA species have been shown to play important regulatory roles in tumorigenesis and cancer development as well. Examples include, but not limited to, mir-574-3p and prostate cancer[38], mir-23a and gastric cancer[39], mir-21 and colon cancer [40]. Based upon the abundant data accumulated during the past two decades, scientists began to argue for use of microRNAs as novel therapeutic targets for various malignancies[41]. "
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    Preview · Article · Sep 2013 · PLoS ONE
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    • "miR-574- 3p controls Bcl-xL and notably induces apoptosis in prostate cancer cells. miR-574-3p is underexpressed in prostate cancer cells, and it has been shown that cells treated with genistein demonstrated an increase in the expression of miR-574-3p (Chiyomaru et al. 2013). Polycomb group gene Bmi-1 is overexpressed in prostate cancer stem cells; however, it has previously been shown that cells treated with NVP-LDE-225 (erismodegib) remarkably displayed a decrease in the expression of Bmi-1. "
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    • "ARHGDIA negatively regulates the Rho family of GTPases (Rho, Rac, and Cdc42) [21] that are involved in the WNT signaling pathway [22]. We also found that genistein down-regulates the RAC1 and EP300 genes that are important regulators of VEGF-mediated angiogenesis [23], [24] and the EGFR gene by up-regulating miR-574-3p [25]. "
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