Investigation of a Putative Estrogen-Imprinting Gene, Phosphodiesterase Type IV Variant (Pde4d4), in Determining Prostate Cancer Risk; Final rept. 15 Mar 2006-14 Mar 2008

摘要

Estrogens are known to play a role in the initiation and progression of prostate cancer. Recently, environmental factors such as xenoestrogens have been reported on their prevalence of prostate diseases or cancers. Estrogen imprinting of the prostate gland is believed to associate with an increased incidence of prostatic lesions including inflammation, epithelial hyperplasia, squamous metaplasia, dysplasia and adenocarcinoma. And DNA methylation may be one of the possible mechanisms of the prostate reprogramming. By using one of the global methylation profiling techniques, MSRF, a gene called phosphodiesterase type IV variant 4 (PDE4D4) was shown to be hypomethylated following neonatal exposure to estradiol (EB) or bisphenol A (BPA). We further confirmed the persistence of PDE4D4 promoter hypomethylation and gene up- regulation in the adult life by using bisulfite genomic sequencing and real- time PCR. PDE4D4 has function of cAMP-degradation to maintain the second messenger, cAMP, in a narrow range of concentrations that is critical for growth and differentiation of the hormone target cells by activating several downstream signaling molecules. Taken together, these findings supported that PDE4D4 dysregulation, via CpG island hypomethylation, at its promoter regions in early life, by EB or BPA, can alter its expression and activity of the gene. Present data also suggested that PDE4D4 can be used as a biomarker for prostate cancer assessment.