Dai Yuhu, Ren Dong, Yang Qing, Cui Yanmei, Guo Wei, Lai Yingrong, Du Hong, Lin Chuyong, Li Jun, Song Libing, Peng Xinsheng
Department of Orthopaedic Surgery, The First Affiliated Hospital of Sun Yat-sen University, 58# Zhongshan 2rd Road, Guangzhou 510080, China.
Guangdong Provincial Key Laboratory of Orthopedics and Traumatology, 58# Zhongshan 2rd Road, Guangzhou 510080, Guangdong Province, China.
Br J Cancer. 2017 Aug 22;117(5):685-694. doi: 10.1038/bjc.2017.212. Epub 2017 Jul 11.
Backgroud:Constitutive activation of TGF-β signalling is a well-recognised mechanism in bone metastasis of prostate cancer (PCa). Protein Interacting with PRKCA 1 (PICK1) is a critical negative regulator of the TGF-β pathway. However, the clinical significance and biological role of PICK1 in PCa bone metastasis remain obscure.
PICK1 expression is evaluated by immunohistochemistry (IHC) in 198 PCa patients. Statistical analysis is performed to explore correlation between PICK1 expression and clinicopathological features in PCa patients. The biological role of PICK1 is examined in PC-3 and C4-2B cells in vitro and a mouse intracardial model in vivo.
PICK1 expression is decreased in PCa tissues with bone metastasis and bone-derived cells and downregulation of PICK1 positively correlates with serum PSA level, Gleason grade and bone metastasis status in PCa patients. Overexpression of PICK1 suppresses PCa cell invasion and migration in vitro and bone metastasis in vivo. Our results further indicate downregulation of PICK1 is caused by miR-210-3p overexpression in PCa tissues with bone metastasis. Clinical negative correlation of PICK1 with miR-210-3p is confirmed in PCa tissues.
Our findings uncover a novel functionally and clinically relevant epigenetic regulatory mechanism for constitutive activation of TGF-β signalling in bone metastasis of PCa.
背景：转化生长因子-β（TGF-β）信号通路的组成性激活是前列腺癌（PCa）骨转移中一种公认的机制。与蛋白激酶Cα相互作用蛋白1（PICK1）是TGF-β信号通路的关键负调节因子。然而，PICK1在PCa骨转移中的临床意义和生物学作用仍不清楚。
采用免疫组织化学（IHC）法检测198例PCa患者的PICK1表达。进行统计学分析以探讨PICK1表达与PCa患者临床病理特征之间的相关性。在体外PC-3和C4-2B细胞以及体内小鼠心内模型中研究PICK1的生物学作用。
在发生骨转移的PCa组织和骨来源细胞中PICK1表达降低，PICK1的下调与PCa患者的血清前列腺特异抗原（PSA）水平、Gleason分级和骨转移状态呈正相关。PICK1的过表达在体外抑制PCa细胞的侵袭和迁移，在体内抑制骨转移。我们的结果进一步表明，在发生骨转移的PCa组织中，PICK1的下调是由miR-210-3p的过表达引起的。在PCa组织中证实了PICK1与miR-210-3p的临床负相关。
我们的研究结果揭示了一种新的在功能和临床上与PCa骨转移中TGF-β信号通路组成性激活相关的表观遗传调控机制。
