Sonic hedgehog and androgen signaling in tumor and stromal compartments drives epithelial-mesenchymal transition in prostate cancer

Objective. Sonic hedgehog (Shh) signaling, androgens and epithelial-mesenchymal transition (EMT) are related to prostate cancer (PCa) progression. The aim of this study was to investigate how Shh and androgen [dihydrotestosterone (DHT)] signaling act in prostate epithelial and stromal compartments and whether this signaling pathway drives EMT and promotes PCa progression. Material and methods. LNCaP, normal prostate fibroblast (NPF) and cancer-associated prostate fibroblast (CPF) cells were studied with DHT and/or the Shh signaling inhibitor cyclopamine. Real-time reverse transcription-polymerase chain reaction (RT-PCR) was performed to evaluate the expressions of a potential Shh target gene, osteonectin (ON) and EMT-associated markers (E-cadherin, N-cadherin and vimentin). Immunohistochemical studies using PCa prostatectomy samples were performed to assess the expression levels of ON, Gli-1, androgen receptor, Shh, E-cadherin, N-cadherin and vimentin. Results. While DHT enhanced cell proliferation in CPF more than LNCaP or NPF, cyclopamine inhibited cell proliferation enhanced by DHT in CPF. Real-time RT-PCR showed whereas both Shh and DHT induced N-cadherin and vimentin, DHT also induced the expression of osteonectin in LNCaP and cyclopamine blocked these expressions in osteonectin, N-cadherin and vimentin (p = 0.0084, 0.0002 and 0.0373, respectively). Immunohistochemistry showed that high expression of stromal, but, not epithelial, ON was significantly correlated with serum prostate-specific antigen (PSA) (p = 0.031), and high expression of Gli-1 and low expression of stromal ON with PSA recurrence (p = 0.0114 and p = 0.0005, respectively). Conclusions. Shh and androgen signaling in prostate tumor and stromal compartments drives EMT, and thus may play some role in PCa progression. Cyclopamine may be one therapeutic strategy for PCa.