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-β/SMAD signaling by upregulating TGFBR1 expression via sponging miR-324-5p. In turn, TGF-β 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-β 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-β 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-β signaling.

中文翻译：

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lncRNA PCAT7和TGF-β信号转导之间的SMAD3 / SP1复合物介导的组成性活性环促进前列腺癌骨转移。

前列腺癌（PCa）患者的骨转移与癌症相关的死亡有关。长非编码RNA（lncRNA）在PCa的肿瘤进展中起关键作用。尽管如此，lncRNA在PCa骨转移中的生物学功能仍不清楚。通过分析TCGA数据集，PCAT7被鉴定为与骨转移相关的lncRNA。同时，发现PCAT7在具有骨转移的原发性PCa组织中升高，并且与骨转移状态和PCa患者的预后不良有关。从功能上讲，我们的结果表明PCAT7的过度表达促进了PCa体内的骨转移，以及PCa细胞的体外迁移，侵袭和EMT。相反，PCAT7敲低具有相反的作用。从机制上讲，PCAT7通过使海绵状miR-324-5p上调TGFBR1表达来激活TGF-β/ SMAD信号传导。反过来，TGF-β信号通过SMAD3 / SP1复合物诱导的PCAT7上调与PCAT7形成正反馈回路。最后，在PCa组织和临床原代PCa细胞中进一步证明了PCAT7与TGFBR1和TGF-β信号传导活性之间的临床正相关，与miR-324-5p的负相关。这项研究揭示了一种新的机制，该机制负责PCa骨转移中TGF-β信号的组成性激活，这暗示PCAT7可以通过破坏PCAT7和TGF-β之间的组成性活性环来充当针对PCa骨转移的潜在治疗靶标。信号。在PCa组织和临床原代PCa细胞中进一步证实了与miR-324-5p的负相关。这项研究揭示了一种新的机制，该机制负责PCa骨转移中TGF-β信号的组成性激活，这暗示PCAT7可以通过破坏PCAT7和TGF-β之间的组成性活性环来充当针对PCa骨转移的潜在治疗靶标。信号。在PCa组织和临床原代PCa细胞中进一步证明了与miR-324-5p的负相关。这项研究揭示了一种新的机制，该机制负责PCa骨转移中TGF-β信号的组成性激活，这暗示PCAT7可以通过破坏PCAT7和TGF-β之间的组成性活性环来充当针对PCa骨转移的潜在治疗靶标。信号。