Autocrine and Paracrine Hh Signaling Regulate Prostate Development.

摘要

Hedgehog (Hh) signaling has been reported to play an important role in prostate development and prostate cancer. Studies from several laboratories have shown that Hh ligands are expressed in the epithelium of the developing prostate; activate Hh target genes expressed in the surrounding mesenchyme and influence prostate ductal growth. However, publications from these different laboratories have reported conflicting effects on growth. One major goal of this research was to elucidate the reason for those conflicting data. We addressed this issue by: 1) Defining Hh mesenchymal responsive genes in fetal prostate by microarray; 2) Characterizing epithelial growth effects of Hh signaling pre- and postnatal in both in vitro explants culture and in vivo transgenic mice model; 3) Proposing the potential molecular mechanisms underlying this growth regulation by Hh signaling. Herein, we identify a total of 89 genes that are regulated by Hh signaling in UGSM-2 cell line, the immortalized mesenchymal cells from the E16 UGS mesenchyme. We observe stagespecific growth effects of Hh signaling. Specifically, Hh pathway activation stimulates epithelial proliferation prenatally, while inhibits epithelial proliferation postanatally. We propose this temporal growth effects is mediated by the discordant regulation of a subset of target genes by Hh signaling in the prenatal and postnatal prostate. In addition, we provide the evidence of autocrine Hh signaling in the developing prostate and identify its potential role in maintaining a progenitor cell population. The findings of this research resolve the long-term discrepancies on growth effects of Hh signaling in the developing prostate, and provide a novel interpretation of both autocrine and paracrine Hh signaling mechanism in regulating prostate development, which will offer critically important insight into the actions of Hh signaling in advanced prostate cancer.