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

Abstract

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.