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 overexpressed 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. THAP9-AS1/YAP axis may serve as a potential biomarker and therapeutic target for PDAC treatment.

中文翻译：

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lncRNA THAP9-AS1促进胰腺导管腺癌的生长，并通过使miR-484变海绵并与YAP相互作用而导致不良的临床结果。

目的已在各种癌症类型中观察到长的非编码RNA（lncRNA）。我们对现有数据库的生物信息学分析表明，lncRNA THAP9-AS1在胰腺导管腺癌（PDAC）中过表达。我们旨在研究THAP9-AS1在PDAC中的作用和机制。实验设计胰腺癌患者样品中THAP9-AS1过表达的特征在于临床结果。验证了THAP9-AS1的非蛋白质编码特性。进行了各种体外和体内实验，以研究THAP9-AS1与YAP信号传导之间的相互作用。结果我们证明了lncRNA THAP9-AS1在多个患者样本集中的PDAC中过表达，这与PDAC患者的不良预后显着相关。THAP9-AS1在体外和体内均可促进PDAC细胞的生长。THAP9-AS1通过增强YAP信号传导发挥作用。异位YAP表达克服了THAP9-AS1敲低的影响。相反，YAP组合式降低了THAP9-AS1过表达的影响。THAP9-AS1作为miR-484的竞争性内源RNA，导致YAP上调。此外，THAP9-AS1与YAP蛋白结合并抑制LATS1磷酸化介导的YAP失活。相反，YAP / TEAD1复合物促进THAP9-AS1转录以形成前馈电路。重要的是，THAP9-AS1水平与PDAC组织中的YAP表达正相关。YAP过表达还预示了PDAC患者的预后不良。结论我们的研究结果表明THAP9-AS1通过增强YAP信号传导在PDAC生长中发挥重要作用，反过来也调节THAP9-AS1转录。THAP9-AS1 / YAP轴可能用作PDAC治疗的潜在生物标志物和治疗靶标。