REST 通过下调 miR-133b 促进前列腺癌骨转移，从而激活 TGF-β 信号通路。
Transcriptional downregulation of miR-133b by REST promotes prostate cancer metastasis to bone via activating TGF-β signaling.
机构信息
Department of Orthopaedic Surgery, the Second Affiliated Hospital of Guangzhou Medical University, 510260, Guangzhou, China.
Department of Orthopaedic Surgery, the First Affiliated Hospital of Sun Yat-sen University, 510080, Guangzhou, China.
出版信息
Cell Death Dis. 2018 Jul 13;9(7):779. doi: 10.1038/s41419-018-0807-3.
High avidity of bone metastasis is an important characteristic in prostate cancer (PCa). Downexpression of miR-133b has been reported to be implicated in the development, progression and recurrence in PCa. However, clinical significance and biological roles of miR-133b in bone metastasis of PCa remain unclear. Here we report that miR-133b is downregulated in PCa tissues and further decreased in bone metastatic PCa tissues. Downexpression of miR-133b positively correlates with advanced clinicopathological characteristics and shorter bone metastasis-free survival in PCa patients. Upregulating miR-133b inhibits invasion, migration in vitro and bone metastasis in vivo in PCa cells. Mechanistically, we find that miR-133b suppresses activity of TGF-β signaling via directly targeting TGF-β receptor I and II, which further inhibits bone metastasis of PCa cells. Our results further reveal that overexpression of REST contributes to miR-133b downexpression via transcriptional repression in PCa tissues. Importantly, silencing miR-133b enhances invasion and migration abilities in vitro and bone metastasis ability in vivo in REST-silenced PCa cells. The clinical correlation of miR-133b with TGFBRI, TGFBRII, REST and TGF-β signaling activity is verified in PCa tissues. Therefore, our results uncover a novel mechanism of miR-133b downexpression that REST transcriptionally inhibits miR-133b expression in PCa cells, and meanwhile support the notion that administration of miR-133b may serve as a rational regimen in the treatment of PCa bone metastasis.
高亲和力的骨转移是前列腺癌（PCa）的一个重要特征。miR-133b 的下调已被报道与 PCa 的发展、进展和复发有关。然而，miR-133b 在 PCa 骨转移中的临床意义和生物学作用仍不清楚。在这里，我们报告 miR-133b 在 PCa 组织中下调，并且在骨转移性 PCa 组织中进一步降低。miR-133b 的下调与 PCa 患者的晚期临床病理特征和较短的骨转移无复发生存期呈正相关。上调 miR-133b 抑制 PCa 细胞的体外侵袭、迁移和体内骨转移。从机制上讲，我们发现 miR-133b 通过直接靶向 TGF-β 受体 I 和 II 抑制 TGF-β 信号通路的活性，从而进一步抑制 PCa 细胞的骨转移。我们的研究结果进一步揭示了 REST 通过在 PCa 组织中的转录抑制导致 miR-133b 的下调。重要的是，在沉默 REST 的 PCa 细胞中，沉默 miR-133b 增强了体外的侵袭和迁移能力以及体内的骨转移能力。miR-133b 与 TGFBRI、TGFBRII、REST 和 TGF-β 信号活性的临床相关性在 PCa 组织中得到验证。因此，我们的研究结果揭示了 miR-133b 下调的一种新机制，即 REST 通过在 PCa 细胞中转录抑制 miR-133b 的表达，同时支持给予 miR-133b 可能作为治疗 PCa 骨转移的合理方案的观点。
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