Neonatal exposure to high doses of 17β-estradiol results in inhibition of heparanase-1 expression in the adult prostate

Abstract

Heparanase-1 (HPSE-1) is an endoglycosidase that cleaves heparan sulfate. The physiological functions of HPSE-1 include embryo development, hair growth, wound healing, tumor growth, angiogenesis, metastasis, and inflammation. HPSE-1 expression was found to increase temporarily in the rat ventral prostate (VP) after castration. The promoter region of the Hpse-1 gene has estrogen-responsive elements, suggesting that the gene is regulated by estrogens. In this study, we investigated the expression of HPSE-1 in the VP of 90-day-old rats after neonatal exposure to a high dose of 17β-estradiol. HPSE-1 was not found by immunohistochemistry in the epithelium of estrogenized animals. To determine whether inhibition of Hpse-1 expression in the epithelium was due to pre- or post-transcriptional regulation, epithelial cells were isolated by centrifugation in Percoll gradient and the presence of Hpse-1 mRNA was investigated by RT-PCR. Hpse-1 mRNA was not detected in the estrogenized animals. Considering that Hpse-1 transcription could be inhibited by DNA methylation, we used the methylation-sensitive restriction enzyme HpaII and PCR to show that a single CCGG site at position +185 was more frequently methylated in the epithelium of estrogenized than in control animals. Immunohistochemistry for 5-methylcytidine revealed that the epithelial cell nuclei in estrogenized animals were heavily methylated. These results suggest that Hpse-1 expression was blocked in the epithelial cells of the VP, by estrogen imprinting by a pre-transcriptional mechanism involving DNA methylation.

Dual action of high estradiol doses on MNU‐induced prostate neoplasms in a rodent model with high serum testosterone: Protective effect and emergence of unstable epithelial microenvironment

“…DNA methylation is critical for the regulation of multiple cellular events and has been implicated at a global and local level in carcinogenesis . Estrogen treatment leads to overall prostate epithelium hypermethylation in both analyzed prostate lobes as has been previously described in Wistar rats . On the other hand, after administration of the carcinogen alone, VL epithelium suffered hypomethylation while DL showed an augmentation in 5mC immunostaining.…”

Transcriptome Reveals Long Non-coding RNAs and mRNAs Involved in Primary Wool Follicle Induction in Carpet Sheep Fetal Skin

“…These pathways were found to be important in hair and feather follicle morphogenesis and skin development ( Jung et al, 1998 ; Noramly and Morgan, 1998 ; Huelsken et al, 2001 ; Andl et al, 2002 ; Pummila et al, 2007 ; Michon et al, 2008 ; Xu et al, 2013 ; Zhu et al, 2013 ; Pan et al, 2015 ). Of these predicted targets, EDARADD, FGFR2, HPSE, LRP4, SHH, SOSTDC1, TFAP2C , and TP63 were differentially expressed during induction of primary wool follicles and were found to play important roles in hair follicle development and morphogenesis ( Table 3 ; Sutton and van Bokhoven, 1993 ; Li et al, 2001 ; Thesleff and Mikkola, 2002 ; Wang et al, 2008 ; Augusto et al, 2011 ; Cui et al, 2011 ; Narhi et al, 2012 ; Ahn et al, 2013 ; Mukhopadhyay et al, 2013 ).…”

Distribution of heparan sulfate correlated with the expression of heparanase‐1 and matrix metalloproteinase‐9 in an ovariectomized rats skin

“…Four putative estrogen‐response elements in the heparanase‐promoter region seem to be involved with increased response through estrogen‐receptor in MCF‐7 human breast carcinoma (Elkin et al, 2003). Morever, heparanase expression was blocked in the epithelial cells of prostate by involving DNA methylation (Augusto et al, 2011). Heparanase is differentially expressed in the endometrium menstrual phases.…”