Department of Urologic Surgery, Vanderbilt University Medical Center, Nashville, TN, USA.
Oncogene. 2011 Apr 21;30(16):1868-79. doi: 10.1038/onc.2010.560. Epub 2010 Dec 13.
Our previous studies have found that activation of Wnt/β-catenin signaling resulted in mouse prostatic intraepithelial neoplasia (mPIN). In the large probasin promoter directed SV40-large T-antigen (LPB-Tag) expressing mouse prostate, mPIN forms with rare areas of adenocarcinoma. Combining expression of both Wnt-signaling and Tag expression in the mouse prostate, we have studied the role of Wnt/β-catenin signaling in the progression from mPIN to adenocarcinoma. Our results show that the prostates of mice expressing Tag alone or nuclear β-catenin alone developed mPIN, whereas the activation of both Tag and the Wnt/β-catenin pathway resulted in invasive prostate adenocarcinoma. Furthermore, Foxa2, a forkhead transcription factor, was induced by active Wnt/β-catenin signaling, and the expression of Foxa2 was associated with the invasive phenotype in the primary prostate cancer. In the LPB-Tag/dominant active (DA) β-catenin prostates, MMP7, a Wnt/β-catenin target gene, was upregulated. Furthermore, we also assessed AR and AR signaling pathway in these LPB-Tag/DA β-catenin mice. Although β-catenin is a well-known AR co-activator in vitro, our study provides strong in vivo evidences indicating that both AR protein and the AR pathway were downregulated in the prostate of LPB-Tag/DA β-catenin mice. Histological analysis shows that prostate sections derived from the LPB-Tag/DA β-catenin mice display neuroendocrine differentiation (NED), but NE cancer does not develop. Together, our findings indicate that Wnt/β-catenin signaling has an important role in the progression of mPIN to prostate adenocarcinoma.
我们之前的研究发现，Wnt/β-catenin 信号的激活导致了小鼠前列腺上皮内瘤变（mPIN）。在大前白蛋白启动子指导的 SV40 大 T 抗原（LPB-Tag）表达的小鼠前列腺中，mPIN 与罕见的腺癌区域形成。在小鼠前列腺中同时表达 Wnt 信号和 Tag 表达，我们研究了 Wnt/β-catenin 信号在从 mPIN 向腺癌进展中的作用。我们的结果表明，单独表达 Tag 或核 β-catenin 的小鼠前列腺会发展出 mPIN，而同时激活 Tag 和 Wnt/β-catenin 途径则会导致侵袭性前列腺腺癌。此外，叉头转录因子 Foxa2 被活性 Wnt/β-catenin 信号诱导，Foxa2 的表达与原发性前列腺癌的侵袭表型相关。在 LPB-Tag/显性激活（DA）β-catenin 前列腺中，MMP7，一个 Wnt/β-catenin 靶基因，被上调。此外，我们还在这些 LPB-Tag/DA β-catenin 小鼠中评估了 AR 和 AR 信号通路。尽管β-catenin 在体外是众所周知的 AR 共激活因子，但我们的研究提供了强有力的体内证据，表明在 LPB-Tag/DA β-catenin 小鼠的前列腺中，AR 蛋白和 AR 通路都被下调。组织学分析表明，来自 LPB-Tag/DA β-catenin 小鼠的前列腺切片显示神经内分泌分化（NED），但没有发展出神经内分泌癌。总之，我们的发现表明，Wnt/β-catenin 信号在 mPIN 向前列腺腺癌的进展中具有重要作用。
