miR-573 inhibits prostate cancer metastasis by regulating epithelial-mesenchymal transition
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Lin Wang1, Guanhua Song2, Weiwei Tan3, Mei Qi3, Lili Zhang3, Jonathan Chan4, Jindan Yu5, Jinxiang Han1, Bo Han3,6
1Research Center for Medicinal Biotechnology, Key Laboratory for Rare & Uncommon Diseases of Shandong Province, Shandong Academy of Medicinal Sciences, Jinan, China
2Institute of Basic Medicine, Shandong Academy of Medical Sciences, Jinan, China
3Department of Pathology, Shandong University Medical School, Jinan, China
4Department of Immunology, University of Toronto, Toronto, Ontario, Canada
5Division of Hematology/Oncology, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, USA
6Department of Pathology, Shandong University Qilu Hospital, Jinan, China
Bo Han, e-mail: email@example.com
Jinxiang Han, e-mail: firstname.lastname@example.org
Keywords: prostate cancer, miR-573, FGFR1, GATA3, metastasis
Received: June 16, 2015 Accepted: September 21, 2015 Published: October 03, 2015
The metastastic cascade is a complex process that is regulated at multiple levels in prostate cancer (PCa). Recent evidence suggests that microRNAs (miRNAs) are involved in PCa metastasis and hold great promise as therapeutic targets. In this study, we found that miR-573 expression is significantly lower in metastatic tissues than matched primary PCa. Its downregulation is correlated with high Gleason score and cancer-related mortality of PCa patients (P = 0.041, Kaplan-Meier analysis). Through gain- and loss-of function experiments, we demonstrated that miR-573 inhibits PCa cell migration, invasion and TGF-β1-induced epithelial-mesenchymal transition (EMT) in vitro and lung metastasis in vivo. Mechanistically, miR573 directly targets the fibroblast growth factor receptor 1 (FGFR1) gene. Knockdown of FGFR1 phenocopies the effects of miR-573 expression on PCa cell invasion, whereas overexpression of FGFR1 partially attenuates the functions of miR-573. Consequently, miR-573 modulates the activation of FGFR1-downstream signaling in response to fibroblast growth factor 2 (FGF2). Importantly, we showed that GATA3 directly increases miR-573 expression, and thus down-regulates FGFR1 expression, EMT and invasion of PCa cells in a miR-573-dependent manner, supporting the involvement of GATA3, miR-573 and FGFR1 in controlling the EMT process during PCa metastasis. Altogether, our findings demonstrate a novel mechanism by which miR-573 modulates EMT and metastasis of PCa cells, and suggest miR-573 as a potential biomarker and/or therapeutic target for PCa management.
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