SMAD3/SP1 complex-mediated constitutive active loop between lncRNA PCAT7 and TGF-β signaling promotes prostate cancer bone metastasis
SMAD3/SP1 complex-mediated constitutive active loop between lncRNA PCAT7 and TGF-β signaling promotes prostate cancer bone metastasis
复制标题
SMAD3/SP1 复合物介导的 lncRNA PCAT7 和 TGF-β 信号之间的本构主动环促进前列腺癌骨
DOI：
10.1002/1878-0261.12634
复制
发表时间：
2020-04-01
影响因子：
6.6
通讯作者：
Peng, Xinsheng
中科院分区：
文献类型：
--
作者：
Lang, Chuandong;Dai, Yuhu;Peng, Xinsheng
在前列腺癌患者中，骨转移与癌症相关的死亡有关。长非编码RNA(LncRNAs)在前列腺癌的发生发展中起重要作用。然而，LncRNAs在前列腺癌骨转移中的生物学功能尚不清楚。通过对TCGA数据集的分析，确定PCAT7为与骨转移相关的LncRNA。同时，PCAT7在原发骨转移的PCa组织中表达升高，并与PCa的骨转移状态和预后不良有关。在功能上，我们的结果显示PCAT7过表达促进了体内的PCa骨转移，以及在体外促进了PCa细胞的迁移、侵袭和EMT，而PCAT7的过表达则相反。在机制上，PCAT7通过海绵作用miR-324-5p上调TGFBR1的表达，从而激活转化生长因子-β/SMAD信号转导。反过来，转化生长因子-β信号通过Smad3/SP1复合体诱导的PCAT7上调与PCAT7形成正反馈环。在PCa组织和临床原代PCa细胞中，PCAT7和TGFBR1与转化生长因子-β信号活性呈正相关，与miR-324-5p呈负相关。本研究揭示了转化生长因子-β信号在前列腺癌骨转移中结构性激活的新机制，提示PCAT7可能通过破坏PCAT7和转化生长因子-β信号之间的结构性活性环路而成为治疗前列腺癌骨转移的潜在靶点。
Bone metastasis is associated with cancer-related death in patients with prostate cancer (PCa). Long noncoding RNAs (lncRNAs) play critical roles in tumor progression of PCa. Nevertheless, the biological function of lncRNAs in PCa bone metastasis remains unclear. PCAT7 was identified as a bone metastasis-related lncRNA via analyzing TCGA dataset. Meanwhile, PCAT7 was found to be elevated in primary PCa tissues with bone metastasis and associated with bone metastasis status and poor prognosis of patients with PCa. Functionally, our results reveal that PCAT7 overexpression promotes PCa bone metastasis in vivo, as well as migration, invasion, and EMT of PCa cells in vitro; on the contrary, PCAT7 knockdown has an inverse effect. Mechanistically, PCAT7 activates TGF-beta/SMAD signaling by upregulating TGFBR1 expression via sponging miR-324-5p. In turn, TGF-beta signaling forms a positive feedback loop with PCAT7 via SMAD3/SP1 complex-induced PCAT7 upregulation. Finally, the clinical positive correlation between PCAT7 and TGFBR1 and TGF-beta signaling activity, and the negative association with miR-324-5p are further demonstrated in PCa tissues and clinical primary PCa cells. This study reveals a novel mechanism that is responsible for the constitutive activation of TGF-beta signaling in PCa bone metastasis, implying that PCAT7 can act as a potential therapeutic target against bone metastasis of PCa via disrupting the constitutive active loop between PCAT7 and TGF-beta signaling.