Abstract
BackgroundNumerous studies have shown that long non-coding RNAs (lncRNAs) play key roles during multiple cancer processes, such as cell proliferation, apoptosis, migration and invasion. The previous studies found that NKILA interacted with and suppressed the nuclear translocation of NF-KappaB, which influenced metastasis and prognosis in breast cancer. However the clinical significance and biological role of NKILA in non-small cell lung cancer (NSCLC) remains unknown.MethodsWe examined expression levels of NKILA in 106 pairs of NSCLC tissues and cell lines. The expression level of NKILA after TGF-β1 stimulation also was examined by qRT-PCR and validated by Chromatin immunoprecipitation (ChIP). Gain-of-function and loss-of-function assays were performed to examine the effect of NKILA on proliferation, migration and invasion of NSCLC cells. RNA immunoprecipitation (RIP), western blot and rescue experiments were carried out to reveal the interrelation between NKILA, NF-κB and EMT signal pathway.ResultsThe expression of NKILA was down-regulated in NSCLC cancer tissues compared with matched adjacent noncancerous tissues, and lower NKILA expression in tumor tissues were significantly correlated with lymph node metastasis and advanced TNM stage. We found that the expression of NKILA was mainly regulated by classical TGF-β signal pathway in NSCLC cells rather than NF-κB pathway reported in breast cancer. Gain and loss of function assays found that NKILA inhibited migration, invasion and viability of NSCLC cells. Mechanistic study showed that NKILA attenuated Snail expression via inhibiting the phosphorylation of IκBα and NF-κB activation, subsequently suppressed the expression of markers of epithelial-mesenchymal transition process.ConclusionsThe present study found that the expression of NKILA was downregulated in tumor tissues of NSCLC, which improved the metastasis of NSCLC patients. In vitro studies further clarified that the expression of NKILA was regulated through classical TGF-β signal pathway, which subsequently inhibited migration and invasion of NSCLC cells through interfering NF-κB/Snail signal pathway in NSCLC cells.
Highlights
Numerous studies have shown that long non-coding RNAs play key roles during multiple cancer processes, such as cell proliferation, apoptosis, migration and invasion
The results showed that the expression of NF-KappaB Interacting LncRNA (NKILA) was significantly downregulated in tumor tissues compared with the adjacent normal tissues in these 106 non-small cell lung cancer (NSCLC) patients (p < 0.001, Fig. 1a and b)
The expression of NKILA was much lower in NSCLC cell lines derived from metastatic sites than that derived from primary sites (Fig. 1e)
Summary
Numerous studies have shown that long non-coding RNAs (lncRNAs) play key roles during multiple cancer processes, such as cell proliferation, apoptosis, migration and invasion. The clinical significance and biological role of NKILA in non-small cell lung cancer (NSCLC) remains unknown. The Metastasis-associated lung adenocarcinoma transcript 1 (MALAT1), one of the most highly abundant lncRNAs, was upregulated in NSCLC and correlated with metastasis. The overexpression of MALAT1 can promote the metastasis of lung cancer cells by regulate downstream gene expression and alternative splicing [7]. The long non-coding RNA PVT1 suppressed cell growth and induced apoptosis by binding to the enhancer of zeste homolog 2 (EZH2) protein, a histone methyltransferase of the PRC2 complex, in NSCLC [8]. Even the exact mechanism of lncRNAs still unknown, most of the lncRNAs exert bio-function via interact with other molecules [9] including mRNA, miRNA, genome DNA, other lncRNAs and mostly proteins, especially proteins in vital signal pathways
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