HnRNP-F regulates EMT in bladder cancer by mediating the stabilization of Snail1 mRNA by binding to its 3′ UTR
HnRNP-F regulates EMT in bladder cancer by mediating the stabilization of Snail1 mRNA by binding to its 3′ UTR
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DOI：
10.1016/j.ebiom.2019.06.017
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发表时间：
2019-07-01
期刊：
影响因子：
11.1
通讯作者：
Tan, Wanlong
中科院分区：
文献类型：
--
作者：
Li, Fei;Zhao, Hongfan;Tan, Wanlong
背景：异质性核糖核蛋白F（hnRNP - F）与多种癌症有关，表明其在肿瘤发生中起作用，但hnRNP - F在膀胱癌（BC）中潜在的致癌作用及机制仍未完全明确。
方法：通过蛋白质组学方法鉴定hnRNP - F。分析103例膀胱癌患者中hnRNP - F表达与预后的相关性。然后，我们应用体外和体内方法揭示hnRNP - F在膀胱癌肿瘤发生中的行为。此外，通过RNA免疫沉淀（RIP）检测hnRNP - F与Snail1 mRNA之间的相互作用，并在用放线菌素D处理后测量Snail1 mRNA的稳定性。最后，通过构建Snail1 mRNA截短体和突变体验证hnRNP - F与Snail1 mRNA之间的结合域。
发现：hnRNP - F在膀胱癌组织中显著上调，其表达增加与膀胱癌患者预后不良相关。hnRNP - F对肿瘤生长是必需的，可诱导膀胱癌中的上皮 - 间质转化（EMT）和转移。当hnRNP - F被沉默或增强时，Snail1在mRNA和蛋白质水平的表达变化均与hnRNP - F呈正相关，这表明Snail1可能是hnRNP - F的下游靶点，介导其对增强膀胱癌侵袭、转移和EMT的作用。hnRNP - F的过表达导致Snail1 mRNA稳定性增加。我们的RNA芯片分析显示hnRNP - F可与Snail1 mRNA结合，并且我们进一步证明hnRNP - F可直接结合到Snail1 mRNA的3'非翻译区（3' UTR）以增强其稳定性。
解释：我们的研究结果表明，hnRNP - F通过结合到Snail1 mRNA的3' UTR介导Snail1 mRNA的稳定，随后调节EMT。（C）2019由爱思唯尔B.V.出版
Background: Heterogeneous nuclear ribonucleoprotein F (hnRNP-F) has been implicated inmultiple cancers, suggesting its role in tumourigenesis, but the potential oncogenic role and mechanismof hnRNP-F in bladder cancer (BC) remain incompletely understood.Methods: HnRNP-F was identified by proteomic methods. A correlation of hnRNP-F expression with prognosis was analysed in 103 BC patients. Then, we applied in vitro and in vivo methods to reveal the behaviours of hnRNP-F in BC tumourigenesis. Furthermore, the interaction between hnRNP-F and Snail1 mRNA was examined by RNA immunoprecipitation (RIP), and Snail1 mRNA stability was measured after treatment with actinomycin D. Finally, the binding domain between hnRNP-F and Snail1 mRNA was verified by constructing Snail1 mRNA truncations and mutants.Finding: HnRNP-F is significantly upregulated in BC tissue, and its increased expression is associated with a poor prognosis in BC patients. HnRNP-F is necessary for tumour growth, inducing epithelial-mesenchymal transition (EMT) and metastasis in BC. The changes in Snail1 expression were positively correlated with hnRNP-F at both the mRNA and protein levels when hnRNP-F was silenced or enhanced, suggesting that Snail1 is likely a downstream target of hnRNP-F that mediates its effects on enhancing invasion, metastasis and EMT in BC. The overexpression of hnRNP-F caused an increase in the stability of Snail1 mRNA. Our RNA chip analysis revealed that hnRNP-F could combine with Snail1 mRNA, and we further demonstrated that hnRNP-F could directly bind to the 3' untranslated region (3' UTR) of Snail1 mRNA to enhance its stability.Interpretation: Our findings suggest that hnRNP-F mediates the stabilization of Snail1 mRNA by binding to its 3' UTR, subsequently regulating EMT. (C) 2019 Published by Elsevier B.V.