Abstract
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.
Highlights
Metastasis is often responsible for the recurrence, poor prognosis and death of prostate cancer (PCa)
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
For the first time, we demonstrated that miR-573 exhibits a stepwise downregulation in BPH, primary PCa tumors and metastatic tissues
Summary
Metastasis is often responsible for the recurrence, poor prognosis and death of prostate cancer (PCa). A better understanding the molecular mechanisms involved in PCa metastasis will contribute to the identification of novel prognostic biomarkers and therapeutic targets [1]. Aberrant expression of many miRNAs has been linked to human diseases including cancers [2]. Like classical oncogenes or tumor suppressors, miRNAs have been shown to play important roles in cancer metastasis [3]. Epithelial-mesenchymal transition (EMT), characterized by the loss of epithelial characteristics and acquisition of a mesenchymal phenotype, plays a critical role in PCa progression and metastasis [4]. Reported molecular mechanisms underlying EMT involve regulation of transcription factors, cellular junctions, cytoskeleton, and miRNAs [4, 5]. Detailed research focusing on miRNAs might reveal novel mechanisms of PCa progression and potential targets for therapeutic intervention
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