Long noncoding RNA NSCLCAT1 increases non-small cell lung cancer cell invasion and migration through the Hippo signaling pathway by interacting with CDH1.

Abstract

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.