lncRNA THAP9-AS1 Promotes Pancreatic Ductal Adenocarcinoma Growth and Leads to a Poor Clinical Outcome via Sponging miR-484 and Interacting with YAP
lncRNA THAP9-AS1 Promotes Pancreatic Ductal Adenocarcinoma Growth and Leads to a Poor Clinical Outcome via Sponging miR-484 and Interacting with YAP
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LncRNA THAP9-AS1 通过海绵 miR-484 并与 YAP 相互作用促进胰腺导管腺癌生长并导致不良的临床结果
DOI：
10.1158/1078-0432.ccr-19-0674
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发表时间：
2020-04-01
影响因子：
11.5
通讯作者：
Zheng, Guopei
中科院分区：
文献类型：
--
作者：
Li, Nan;Yang, Guohua;Zheng, Guopei
目的：在多种癌症类型中观察到长链非编码RNA（lncRNA）。我们对现有数据库的生物信息学分析表明，lncRNA THAP 9-AS 1在胰腺导管腺癌（PDAC）中过表达。本研究旨在探讨THAP 9-AS 1在PDAC.Experimental Design中的作用和机制：研究胰腺癌患者标本中THAP 9-AS 1的过表达情况，并分析其与临床预后的关系。证实了THAP 9-AS 1的非蛋白质编码特性。通过各种体外和体内实验研究THAP 9-AS 1和雅普信号转导之间的相互作用。结果：我们证明了lncRNA THAP 9-AS 1在多个患者样本集中在PDAC中过表达，这与PDAC患者的不良结局显著相关。THAP 9-AS 1在体外和体内均促进PDAC细胞生长。THAP 9-AS 1通过增强雅普信号通路发挥其作用。异位雅普表达克服了THAP 9-AS 1敲低的影响。然而，雅普敲低减弱了THAP 9-AS 1过表达的作用。THAP 9-AS 1作为miR-484的竞争性内源RNA，导致雅普上调。此外，THAP 9-AS 1与雅普蛋白结合并抑制LATS 1对雅普的磷酸化介导的失活。相反，雅普/TEAD 1复合物促进THAP 9-AS 1转录，形成前馈回路。重要的是，PDAC组织中THAP 9-AS 1水平与雅普表达正相关。雅普过表达也预示PDAC.Conclusions患者预后不佳：我们的研究结果表明，THAP 9-AS 1通过增强雅普信号传导，进而调节THAP 9-AS 1转录，在PDAC生长中起重要作用。THAP 9AS 1/雅普轴可能作为PDAC治疗的潜在生物标志物和治疗靶点。
Purpose: Long noncoding RNAs (lncRNA) have been observed in various cancer types. Our bioinformatic analysis of existing databases demonstrated overexpression of lncRNA THAP9-AS1 in pancreatic ductal adenocarcinoma (PDAC). We aimed to investigate the roles and mechanisms of THAP9-AS1 in PDAC.Experimental Design: The overexpression of THAP9-AS1 in samples of patients with pancreatic cancer was characterized and was associated with clinical outcomes. The nonprotein coding property of the THAP9-AS1 was verified. Various in vitro and in vivo experiments were performed to investigate the interaction between THAP9-AS1 and YAP signaling.Results: We demonstrated that lncRNA THAP9-AS1 is over-expressed in PDAC in multiple patient sample sets, which is significantly associated with poor outcome of patients with PDAC. THAP9-AS1 promotes PDAC cells growth both in vitro and in vivo. THAP9-AS1 exerts its effects via enhancing YAP signaling. Ectopic YAP expression overcame the effects of THAP9-AS1 knockdown. Inversely, YAP knockdown diminished the effects of THAP9-AS1 overexpression. THAP9-AS1 acts as a competing endogenous RNA for miR-484, leading to YAP upregulation. Moreover, THAP9-AS1 binds to YAP protein and inhibits the phosphorylation-mediated inactivation of YAP by LATS1. Reciprocally, YAP/TEAD1 complex promotes THAP9-AS1 transcription to form a feed-forward circuit. Importantly, THAP9-AS1 level positively correlates with YAP expression in PDAC tissues. YAP overexpression also predicts a poor outcome in patients with PDAC.Conclusions: Our findings indicate that THAP9-AS1 plays an important role in PDAC growth via enhancing YAP signaling, which in turn also modulates THAP9-AS1 transcription. THAP9AS1/YAP axis may serve as a potential biomarker and therapeutic target for PDAC treatment.