FZD8, a target of p53, promotes bone metastasis in prostate cancer by activating canonical Wnt/β-catenin signaling
FZD8, a target of p53, promotes bone metastasis in prostate cancer by activating canonical Wnt/β-catenin signaling
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FZD8 是 p53 的靶标，通过激活经典 Wnt/β-catenin 信号传导促进前列腺癌骨转移
DOI：
10.1016/j.canlet.2017.05.029
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发表时间：
2017-08-28
期刊：
影响因子：
9.7
通讯作者：
Peng, Xinsheng
中科院分区：
文献类型：
--
作者：
Li, Qiji;Ye, Liping;Peng, Xinsheng
前列腺癌 (PCa) 是男性中第二常见的癌症，并且具有很高的骨转移倾向。目前，骨转移仍然无法治愈，治疗方法也很有限。需要更好地了解 PCa 骨转移所涉及的分子机制，以开发针对该疾病的更有效的治疗方法。在此，我们报道在 FZD 家族中，FZD8 在骨转移 PCa 细胞系和组织中显着上调。高水平的FZD8表达与临床肿瘤进展和骨转移显着正相关。此外，我们发现过表达 FZD8 通过激活典型的 Wnt/β-catenin 信号传导，在体外促进 PCa 细胞迁移、侵袭和干细胞样表型，而沉默 FZD8 则会抑制。重要的是，FZD8的下调极大地抑制了体内PCa骨转移的发生率。此外，野生型p53通过直接与FZD8启动子相互作用来转录抑制FZD8。总而言之，这些发现揭示了 PCa 骨转移的新机制，并表明 FZD8 可能代表 PCa 骨转移的潜在治疗靶点。 (C) 2017 Elsevier B.V. 保留所有权利。
Prostate cancer (PCa) is the second most frequently diagnosed cancer among men and exhibits a high propensity to metastasize to bone. Currently, bone metastasis remains incurable, and therapies are limited. A better understanding of the molecular mechanisms involved in PCa bone metastasis is needed to develop more effective therapeutics for this disease. Herein, we reported that among the FZD family, FZD8 was robustly upregulated in bone-metastastic PCa cell lines and tissues. High levels of FZD8 expression were significantly positively associated with clinical tumor progression and bone metastasis. Furthermore, we found that overexpressing FZD8 promoted, whereas silencing FZD8 suppressed, PCa cell migration, invasion and stem cell-like phenotypes in vitro, through the activation of canonical Wnt/beta-catenin signaling. Importantly, downregulation of FZD8 greatly suppressed the incidence of PCa bone metastasis in vivo. Moreover, wild-type p53 transcriptionally repressed FZD8 by directly interacting with the FZD8 promoter. Taken together, these findings uncover a novel mechanism for PCa bone metastasis, and indicate that FZD8 might represent a potential therapeutic target for PCa bone metastasis. (C) 2017 Elsevier B.V. All rights reserved.