Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
Sci Signal. 2017 Sep 19;10(497):eaah3941. doi: 10.1126/scisignal.aah3941.
Large-scale, genome-wide studies report that RNA binding proteins are altered in cancers, but it is unclear how these proteins control tumor progression. We found that the RNA-editing protein ADAR (adenosine deaminase acting on double-stranded RNA) acted as a facilitator of lung adenocarcinoma (LUAD) progression through its ability to stabilize transcripts encoding focal adhesion kinase (FAK). In samples from 802 stage I LUAD patients, increased abundance of ADAR at both the mRNA and protein level correlated with tumor recurrence. Knocking down ADAR in LUAD cells suppressed their mesenchymal properties, migration, and invasion in culture. Analysis of gene expression patterns in LUAD cells identified ADAR-associated enrichment of a subset of genes involved in cell migration pathways; among these, is the most notable gene whose expression was increased in the presence of ADAR. Molecular analyses revealed that ADAR posttranscriptionally increased FAK protein abundance by binding to the transcript and editing a specific intronic site that resulted in the increased stabilization of mRNA. Pharmacological inhibition of FAK blocked ADAR-induced invasiveness of LUAD cells, suggesting a potential therapeutic application for LUAD that has a high abundance of ADAR.
大规模全基因组研究报告称，RNA 结合蛋白在癌症中发生改变，但这些蛋白如何控制肿瘤进展尚不清楚。我们发现，RNA 编辑蛋白 ADAR（双链 RNA 作用的腺苷脱氨酶）通过稳定编码粘着斑激酶 (FAK) 的转录本，充当肺腺癌 (LUAD) 进展的促进剂。在 802 名 I 期 LUAD 患者的样本中，ADAR 在 mRNA 和蛋白水平的丰度增加与肿瘤复发相关。在 LUAD 细胞中敲低 ADAR 可抑制其在培养中的间充质特性、迁移和侵袭。对 LUAD 细胞中基因表达模式的分析确定了 ADAR 与一组参与细胞迁移途径的基因的富集有关；其中，是最显著的基因，其表达在 ADAR 存在的情况下增加。分子分析显示，ADAR 通过结合 转录本并编辑特定的内含子位点，在后转录水平增加 FAK 蛋白丰度，导致 mRNA 稳定性增加。FAK 的药理学抑制阻断了 ADAR 诱导的 LUAD 细胞侵袭性，这表明 ADAR 丰度高的 LUAD 具有潜在的治疗应用。
