Li Qiji, Ye Liping, Zhang Xin, Wang Min, Lin Chuyong, Huang Shuai, Guo Wei, Lai Yingrong, Du Hong, Li Jun, Song Libing, Peng Xinsheng
Department of Orthopaedic Surgery, The First Affiliated Hospital of Sun Yat-sen University, 510080, Guangzhou, Guangdong Province, China.
Department of Experimental Research, State Key Laboratory of Oncology in Southern China, Sun Yat-sen University Cancer Center, 510060, Guangzhou, Guangdong Province, China.
Cancer Lett. 2017 Aug 28;402:166-176. doi: 10.1016/j.canlet.2017.05.029. Epub 2017 Jun 7.
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/β-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.
前列腺癌(PCa)是男性中第二常见的确诊癌症,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。为了开发针对这种疾病更有效的治疗方法,需要更好地了解PCa骨转移所涉及的分子机制。在此,我们报告在FZD家族中,FZD8在骨转移性PCa细胞系和组织中显著上调。高水平的FZD8表达与临床肿瘤进展和骨转移显著正相关。此外,我们发现过表达FZD8促进PCa细胞迁移、侵袭和体外干细胞样表型,而沉默FZD8则抑制这些表型,这是通过激活经典Wnt/β-连环蛋白信号实现的。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,转录抑制FZD8。综上所述,这些发现揭示了PCa骨转移的一种新机制,并表明FZD8可能是PCa骨转移的一个潜在治疗靶点。