Downregulation of miR-141-3p promotes bone metastasis via activating NF-κB signaling in prostate cancer.
Downregulation of miR-141-3p promotes bone metastasis via activating NF-κB signaling in prostate cancer.
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miR-141-3p 的下调通过激活前列腺癌中的 NF-kappaB 信号传导促进骨转移。
DOI：
10.1186/s13046-017-0645-7
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发表时间：
2017-12-04
期刊：
影响因子：
--
通讯作者：
Tang Y
中科院分区：
文献类型：
--
作者：
Huang S;Wa Q;Pan J;Peng X;Ren D;Huang Y;Chen X;Tang Y
临床上，前列腺癌(PCa)表现出很高的骨转移亲和力。MiR-141-3p是一种在癌症中被广泛研究的miRNA，miR-141-3p的下调已被广泛报道参与了几种人类癌症的进展和转移。然而，miR-141-3p在前列腺癌骨转移中的临床意义和生物学作用尚不清楚。应用实时荧光定量聚合酶链式反应技术检测89例非转移性PCa组织和52例转移性PCa组织中miR-141-3p的表达。统计分析miR-141-3p表达水平与PCa临床病理特征的关系。在体外和小鼠体内模型中评价miR-141-3p在PCa骨转移中的生物学作用。通过生物信息学分析、Western印迹、荧光素酶报告和miRNA免疫沉淀等方法，探讨和检测miR-141-3p与其潜在靶点的关系。检测临床PCa组织中miR-141-3p与其靶点的临床相关性。MIR-141-3p在骨转移性PCa组织中的表达低于非骨转移性PCa组织。MiR-141-3p的低表达与前列腺癌患者血清PSA水平、Gleason分级及骨转移状态呈正相关。此外，上调miR-141-3p可抑制体外培养的PCa细胞的EMT、侵袭和迁移。相反，沉默miR-141-3P会产生相反的效果。重要的是，上调miR-141-3p显著减少了体内PC-3细胞的骨转移。我们的结果进一步表明，miR-141-3p通过直接靶向肿瘤坏死因子受体相关因子5(TRAF5)和TRAF6(TRAF6)来抑制NF-κB信号的激活，从而进一步抑制PCa细胞的侵袭、迁移和骨转移。PCa组织中miR141-3p的表达与TRAF5、TRAF6和NF-κB信号活性呈负相关。我们的发现揭示了前列腺癌骨转移的新机制，提示miR-141-3p模拟物可能成为治疗前列腺癌骨转移的潜在途径。本文的在线版本(10.1186/s13046-017-0645-7)包含补充材料，可供授权用户使用。
Clinically, prostate cancer (PCa) exhibits a high avidity to metastasize to bone. miR-141-3p is an extensively studied miRNA in cancers and downregulation of miR-141-3p has been widely reported to be involved in the progression and metastasis of several human cancer types. However, the clinical significance and biological roles of miR-141-3p in bone metastasis of PCa are still unclear. miR-141-3p expression was examined in 89 non-bone metastatic and 52 bone metastatic PCa tissues by real-time PCR. Statistical analysis was performed to investigate the clinical correlation between miR-141-3p expression levels and clinicopathological characteristics in PCa patients. The biological roles of miR-141-3p in bone metastasis of PCa were evaluated both in vitro and a mouse intracardial model in vivo. Bioinformatics analysis, Western blot, luciferase reporter and miRNA immunoprecipitation assays were performed to explore and examine the relationship between miR-141-3p and its potential targets. Clinical correlation of miR-141-3p with its targets was examined in clinical PCa tissues. miR-141-3p expression is reduced in bone metastatic PCa tissues compared with non-bone metastatic PCa tissues. Low expression of miR-141-3p positively correlates with serum PSA levels, Gleason grade and bone metastasis status in PCa patients. Furthermore, upregulating miR-141-3p suppresses the EMT, invasion and migration of PCa cells in vitro. Conversely, silencing miR-141-3p yields an opposite effect. Importantly, upregulating miR-141-3p dramatically reduces bone metastasis of PC-3 cells in vivo. Our results further show that miR-141-3p inhibits the activation of NF-κB signaling via directly targeting tumor necrosis factor receptor-associated factor 5(TRAF5) and 6 (TRAF6), which further suppresses invasion, migration and bone metastasis of PCa cells. The clinical negative correlation of miR-141-3p expression with TRAF5, TRAF6 and NF-κB signaling activity is demonstrated in PCa tissues. Our findings unravel a novel mechanism underlying the bone metastasis of PCa, suggesting that miR-141-3p mimics might represent a potential therapeutic avenue for the treatment of PCa bone metastasis. The online version of this article (10.1186/s13046-017-0645-7) contains supplementary material, which is available to authorized users.
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