Department of Thoracic Surgery, China-Japan Union Hospital, Jilin University, Changchun, China.
FASEB J. 2019 Jan;33(1):1151-1166. doi: 10.1096/fj.201800408R. Epub 2018 Aug 27.
Metastatic growth is the leading cause of cancer-related death in non-small cell lung cancer (NSCLC). Metastasis is believed to be initiated by an increase in cell motility mediated by the loss of cell-cell adhesion because of the suppression of E-cadherin [encoded by cadherin 1 ( CDH1)]. However, very little is known about the molecular mechanism of CDH1 regulation. Therefore, we hypothesized that non-small cell lung cancer-associated transcript-1 (NSCLCAT1) suppresses functional CDH1 and mediates the Hippo signaling pathway, resulting in increased cell migration and invasion, and reduced apoptosis. Initially, microarray profiling and target prediction programs were employed to identify whether NSCLCAT1 targets CDH1. Next, quantitative PCR was used to determine the expression pattern of NSCLCAT1 in 114 specimens. The biologic functions of NSCLCAT1 in NSCLC were assessed through the up-regulation and down-regulation of the levels of endogenous NSCLCAT1 with the use of NSCLCAT1 vector or small interfering RNA against NSCLCAT1 in NSCLC cells. Furthermore, the Hippo signaling pathway in NSCLC cells was blocked by applying the verteporfin treatment to have a better understanding on the pivotal role of the Hippo signaling pathway in NSCLC. Microarray expression profiles of long noncoding RNAs, GSE19804 and GSE27262), revealed that NSCLCAT1 was up-regulated in NSCLC. Among patients with NSCLC, we determined that the NSCLCAT1 was robustly induced, whereas CDH1 was suppressed. The luciferase activity determination identified CDH1 as a NSCLCAT1 target. NSCLCAT1 was found to increase cell viability, migration, and invasion and to reduce apoptosis in NSCLC cells. The results from the quantitative PCR and Western blot analysis revealed that NSCLCAT1 modulated the Hippo signaling pathway. Furthermore, the inhibition of the Hippo signaling pathway by verteporfin treatment led to the loss of the effect of NSCLCAT1 on NSCLC cells. In summary, our findings suggested that NSCLCAT1 potentially has a role in NSCLC and NSCLCAT1-mediated regulation of the Hippo signaling pathway through the transcriptional repression of CDH1; therefore, the functional suppression or inhibition of NSCLCAT1 could be used as a novel therapeutic pathway in the control of aggressive and metastatic NSCLC.-Zhao, W., Zhang, L.-N., Wang, X.-L., Zhang, J., Yu, H.-X. Long noncoding RNA NSCLCAT1 increases non-small cell lung cancer cell invasion and migration through the Hippo signaling pathway by interacting with CDH1.
转移性生长是非小细胞肺癌（NSCLC）相关死亡的主要原因。人们认为，由于 E-钙黏蛋白[由钙黏蛋白 1 ( CDH1)编码]的抑制，细胞间黏附的丧失导致细胞运动性增加，从而引发转移。然而，关于 CDH1 调节的分子机制知之甚少。因此，我们假设非小细胞肺癌相关转录物 1 ( NSCLCAT1) 抑制功能性 CDH1 并介导 Hippo 信号通路，导致细胞迁移和侵袭增加，细胞凋亡减少。最初，我们使用微阵列分析和靶标预测程序来确定 NSCLCAT1 是否靶向 CDH1。接下来，使用定量 PCR 确定 114 个标本中 NSCLCAT1 的表达模式。通过使用 NSCLCAT1 载体或针对 NSCLC 细胞中 NSCLCAT1 的小干扰 RNA 上调和下调内源性 NSCLCAT1 的水平，评估 NSCLCAT1 在 NSCLC 中的生物学功能。此外，通过应用 Verteporfin 治疗来阻断 Hippo 信号通路，以更好地了解 Hippo 信号通路在 NSCLC 中的关键作用。长非编码 RNA 的微阵列表达谱（GSE19804 和 GSE27262）表明，NSCLCAT1 在 NSCLC 中上调。在 NSCLC 患者中，我们确定 NSCLCAT1 被强烈诱导，而 CDH1 被抑制。荧光素酶活性测定确定 CDH1 是 NSCLCAT1 的靶标。NSCLCAT1 被发现增加 NSCLC 细胞的活力、迁移和侵袭，并减少细胞凋亡。定量 PCR 和 Western blot 分析的结果表明，NSCLCAT1 调节 Hippo 信号通路。此外，Verteporfin 处理抑制 Hippo 信号通路导致 NSCLCAT1 对 NSCLC 细胞的作用丧失。总之，我们的研究结果表明，NSCLCAT1 可能在 NSCLC 中发挥作用，并且通过转录抑制 CDH1，NSCLCAT1 介导的 Hippo 信号通路的调节；因此，功能性抑制或抑制 NSCLCAT1 可能成为控制侵袭性和转移性 NSCLC 的新治疗途径。-赵，W.，张，L.-N.，王，X.-L.，张，J.，于，H.-X. 长非编码 RNA NSCLCAT1 通过与 CDH1 相互作用增加非小细胞肺癌细胞的侵袭和迁移。
