A large-scale analysis of alternative splicing reveals a key role of QKI in lung cancer
A large-scale analysis of alternative splicing reveals a key role of QKI in lung cancer
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DOI：
10.1016/j.molonc.2016.08.001
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发表时间：
2016-11-01
影响因子：
6.6
通讯作者：
Pio, Ruben
中科院分区：
文献类型：
--
作者：
de Miguel, Fernando J.;Pajares, Maria J.;Pio, Ruben
近年来，人们对癌症中的选择性剪接的理解越来越感兴趣。在这项研究中，我们进行了全基因组分析，以确定非小细胞肺癌中癌症相关的剪接变异体。我们发现并验证了已知与肺癌生物学相关的基因剪接的新差异，如NFIB，ENAH或SPAG 9。基因富集分析揭示了选择性剪接对癌症相关分子功能的重要贡献，特别是那些参与细胞骨架动力学的功能。有趣的是，在我们的分析中发现的改变的基因中有相当一部分是蛋白质震动（QKI）的靶点，指出该因子是非小细胞肺癌中选择性剪接的最相关调节因子之一。我们还发现，ESYT 2，QKI的目标之一，是参与细胞骨架组织。肺癌细胞中ESYT 2-短变体抑制导致肌动蛋白的皮质分布，而长变体的抑制导致内吞作用的增加，这表明ESYT 2的癌症相关剪接模式对癌细胞的生物学具有深远的影响。最后，我们发现非小细胞肺癌中核QKI低表达是无病生存的独立预后因素（HR = 2.47; 95%CI = 1.11-5.46，P = 0.026）。总之，我们确定了几个剪接变异体在肺癌中的功能相关性，主要由剪接因子QKI调节，QKI是一种与肺癌预后相关的肿瘤抑制因子。(C)2016年欧洲生物化学学会联合会。Elsevier B. V.出版，保留所有权利。
Increasing interest has been devoted in recent years to the understanding of alternative splicing in cancer. In this study, we performed a genome-wide analysis to identify cancer-associated splice variants in non-small cell lung cancer. We discovered and validated novel differences in the splicing of genes known to be relevant to lung cancer biology, such as NFIB, ENAH or SPAG9. Gene enrichment analyses revealed an important contribution of alternative splicing to cancer-related molecular functions, especially those involved in cytoskeletal dynamics. Interestingly, a substantial fraction of the altered genes found in our analysis were targets of the protein quaking (QKI), pointing to this factor as one of the most relevant regulators of alternative splicing in non-small cell lung cancer. We also found that ESYT2, one of the QKI targets, is involved in cytoskeletal organization. ESYT2-short variant inhibition in lung cancer cells resulted in a cortical distribution of actin whereas inhibition of the long variant caused an increase of endocytosis, suggesting that the cancer-associated splicing pattern of ESYT2 has a profound impact in the biology of cancer cells. Finally, we show that low nuclear QKI expression in non-small cell lung cancer is an independent prognostic factor for disease-free survival (HR = 2.47; 95% CI = 1.11-5.46, P = 0.026). In conclusion, we identified several splicing variants with functional relevance in lung cancer largely regulated by the splicing factor QKI, a tumor suppressor associated with prognosis in lung cancer. (C) 2016 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.