Long noncoding RNA EGFR-AS1 promotes cell growth and metastasis via affecting HuR mediated mRNA stability of EGFR in renal cancer
Long noncoding RNA EGFR-AS1 promotes cell growth and metastasis via affecting HuR mediated mRNA stability of EGFR in renal cancer
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长非编码RNA EGFR-AS1通过影响肾癌中HuR介导的EGFR mRNA稳定性促进细胞生长和转移
DOI：
10.1038/s41419-019-1331-9
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发表时间：
2019-02-15
影响因子：
9
通讯作者：
Qu, Le
中科院分区：
文献类型：
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作者：
Wang, Anbang;Bao, Yi;Qu, Le
长链非编码RNA（lncRNA）与肾细胞癌（RCC）有关，但在很大程度上仍不清楚。利用公开的肾癌（n = 703）转录组测序数据，并整合生物信息学分析，我们筛选并鉴定了一种有价值的lncRNA，EGFR-AS 1。在我们的验证队列（n = 204）中，EGFR-AS 1在RCC组织中显著上调（P < 0.001）。功能获得和功能丧失研究表明，EGFR-AS 1在体外和体内促进细胞增殖和侵袭。基于先前的研究和EGFR与EGFR-AS 1的序列互补性，我们证明EGFR-AS 1直接结合EGFR mRNA并抑制其降解。此外，RNA pull-down和质谱分析表明，EGFR-AS 1与HuR相互作用，这是负责EGFR的mRNA稳定性。多因素分析显示EGFR-AS 1高表达者预后差（高vs低：P = 0.018，HR = 2.204，95% CI：1.145-4.241）。总之，EGFR-AS 1通过增强HuR介导的EGFR mRNA稳定性来增强RCC细胞的恶性表型。我们的数据也为EGFR-AS 1作为RCC的预后生物标志物和潜在治疗靶点提供了生物学依据。
Long noncoding RNAs (lncRNAs) are implicated in renal cell carcinoma (RCC), but remain largely unclear. Using publicly available transcriptome sequencing data from renal cancer (n = 703) and integrating bioinformatics analyses, we screened and identified a valuable lncRNA, EGFR-AS1. In our validation cohort (n = 204), EGFR-AS1 was significantly upregulated in RCC tissues (P < 0.001). Gain-of-function and loss-of-function studies showed that EGFR-AS1 promoted cell proliferation and invasion in vitro and in vivo. Based on previous studies and sequence complementarity of EGFR with EGFR-AS1, we demonstrated that EGFR-AS1 directly bound to EGFR mRNA and inhibited its degradation. Furthermore, RNA pull-down and mass spectrometry analyses showed that EGFR-AS1 interacted with HuR, which was responsible for the mRNA stability of EGFR. Multivariate analysis suggested that higher EGFR-AS1 expression predicted a poor prognosis in RCC patients (high vs low: P = 0.018, HR = 2.204, 95% CI: 1.145-4.241). In conclusion, EGFR-AS1 enhances the malignant phenotype of RCC cells by enhancing HuR-mediated mRNA stability of EGFR. Our data also provide biological rationales for EGFR-AS1 as a prognostic biomarker and a potential therapeutic target for RCC.