Wnt−11 is a secreted protein that modulates cell growth, differentiation and morphogenesis during development. We previously reported that Wnt−11 expression is elevated in hormone−independent prostate cancer and that the progression of prostate cancer from androgen−dependent to androgen−independent proliferation correlates with a loss of mutual inhibition between Wnt−11− and androgen receptor−dependent signals. However, the prevalence of increased expression of Wnt−11 in patient tumours and the functions of Wnt−11 in prostate cancer cells were not known.

Wnt−11 protein levels in prostate tumours were determined by immunohistochemical analysis of prostate tumour tissue arrays. Wnt−11 protein was elevated in 77/117 of tumours when compared with 27 benign prostatic hypertrophy specimens and was present in 4/4 bone metastases. In addition, there was a positive correlation between Wnt−11 expression and PSA levels above 10 ng/ml. Androgen−depleted LNCaP prostate cancer cells form neurites and express genes associated with neuroendocrine−like differentiation (NED), a feature of prostate tumours that have a poor prognosis. Since androgen−depletion increases expression of Wnt−11, we examined the role of Wnt−11 in NED. Ectopic expression of Wnt−11 induced expression of NSE and ASCL1, which are markers of NED, and this was prevented by inhibitors of cyclic AMP−dependent protein kinase, consistent with the known role of this kinase in NED. Wnt−11 did not induce NSE expression in RWPE−1 cells, which are derived from benign prostate, suggesting that the role of Wnt−11 in NED is specific to prostate cancer. Moreover, silencing of Wnt−11 expression in androgen−depleted LNCaP cells prevented NED and resulted in apoptosis. Silencing of Wnt−11 gene expression in androgen−independent PC3 cells also reduced expression of NSE and increased apoptosis. Finally, silencing of Wnt−11 reduced PC3 cell migration and ectopic expression of Wnt−11 promoted LNCaP cell invasion.

These observations suggest that the increased level of Wnt−11 found in prostate cancer contributes to tumour recurrence by promoting NED, tumour cell survival and cell migration/invasion, and may provide an opportunity for novel therapy in prostate cancer.

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