BACKGROUND The activation of NF-κB signaling pathway is regarded as the dominant process that correlates with tumorigenesis. Recently, increasing evidence shows that long noncoding RNAs (lncRNAs) play crucial roles in sustaining the NF-κB signaling pathway. However, the underlying mechanisms have not yet been elucidated. METHODS The expression and clinical features of PLACT1 were analyzed in a 166-case cohort of PDAC by qRT-PCR and in situ hybridization. The functional role of PLACT1 was evaluated by both in vitro and in vivo experiments. Chromatin isolation by RNA purification assays were utilized to examine the interaction of PLACT1 with IκBα promoter. RESULTS We identified a novel lncRNA-PLACT1, which was significantly upregulated in tumor tissues and correlated with progression and poor survival in PDAC patients. Moreover, PLACT1 promoted the proliferation and invasion of PDAC cells in vitro. Consistently, PLACT1 overexpression fostered the progression of PDAC both in orthotopic and lung metastasis mice models. Mechanistically, PLACT1 suppressed IκBα expression by recruiting hnRNPA1 to IκBα promoter, which led to increased H3K27me3 that decreased the transcriptional level of IκBα. Furthermore, E2F1-mediated overexpression of PLACT1 modulated the progression of PDAC by sustained activation of NF-κB signaling pathway through forming a positive feedback loop with IκBα. Importantly, administration of the NF-κB signaling pathway inhibitor significantly suppressed PLACT1-induced sustained activation of NF-κB signaling pathway, leading to reduced tumorigenesis in vivo. CONCLUSIONS Our findings suggest that PLACT1 provides a novel epigenetic mechanism involved in constitutive activation of NF-κB signaling pathway and may represent a new therapeutic target of PDAC.

中文翻译：

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在胰腺癌中，lncRNA-PLACT1 通过具有 IκBα/E2F1 轴的正反馈回路维持 NF-κB 通路的激活。

背景 NF-κB信号通路的激活被认为是与肿瘤发生相关的主要过程。最近，越来越多的证据表明，长链非编码 RNA (lncRNA) 在维持 NF-κB 信号通路中起着至关重要的作用。然而，潜在的机制尚未阐明。方法通过qRT-PCR和原位杂交在166例PDAC队列中分析PLACT1的表达和临床特征。PLACT1 的功能作用通过体外和体内实验进行了评估。通过 RNA 纯化测定分离染色质用于检查 PLACT1 与 IκBα 启动子的相互作用。结果 我们发现了一种新的 lncRNA-PLACT1，它在肿瘤组织中显着上调，并与 PDAC 患者的进展和不良生存率相关。而且，PLACT1在体外促进PDAC细胞的增殖和侵袭。一致地，PLACT1 过表达促进了 PDAC 在原位和肺转移小鼠模型中的进展。从机制上讲，PLACT1 通过将 hnRNPA1 募集到 IκBα 启动子来抑制 IκBα 表达，这导致 H3K27me3 增加，从而降低了 IκBα 的转录水平。此外，E2F1 介导的 PLACT1 过表达通过与 IκBα 形成正反馈环持续激活 NF-κB 信号通路来调节 PDAC 的进展。重要的是，给予 NF-κB 信号通路抑制剂显着抑制 PLACT1 诱导的 NF-κB 信号通路持续激活，从而减少体内肿瘤发生。