Mechanisms Down-Regulating Sprouty1, a Growth Inhibitor in Prostate Cancer

摘要

The Sprouty gene family negatively regulates growth factor-induced receptor tyrosine kinase signaling in human prostate cancer (PCa). The purpose of this study was to investigate the expression of Sprouty1 in PCa, determine its biological function and elucidate the molecular mechanism(s) regulating its expression in PCa. RESULTS: Using immunohistochemical and quantitative RT-PCR analysis, I have shown that Sprouty1 is down-regulated in PCa tissues compared to matched normal prostate tissues. Transient forced expression of Sprouty1 significantly inhibited PCa proliferation, while stable over-expression of Sprouty1 was deleterious to PCa cell growth. I have shown by pyrosequencing and other methylation assays that DNA methylation of Sprouty1 promoter is a key mechanism for down-regulating Sprouty1 expression in PCa. Transcriptional studies have identified GATA and EGR transcription factors as key transcriptional repressors modulating Sprouty1 expression in PCa. CONCLUSION: I have demonstrated that the expression of Sprouty1, whose gene products encodes for a potential tumor suppressor activity is down-regulated in PCa. I have also shown DNA methylation and transcriptional repression to be key mechanisms for dys-regulating Sprouty1 expression in PCa.