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DLL3 regulates the migration and invasion of small cell lung cancer by modulating Snail.

ABSTRACT: Delta-like protein 3 (DLL3) is a ligand of Notch signaling, which mediates cell-fate decisions and is tumor-suppressive or oncogenic depending on the cellular context. Previous studies show that DLL3 is highly expressed in small cell lung cancer (SCLC) but not in normal lung tissue, suggesting that DLL3 might be associated with neuroendocrine tumorigenesis. However, its role in SCLC remains unclear. To investigate the role of DLL3 in tumorigenesis in SCLC, we performed loss-of-function and gain-of-function assays using SCLC cell lines. In vitro analysis of cell migration and invasion by transwell assay showed that DLL3 knockdown reduced migration and invasion of SCLC cells, whereas DLL3 overexpression increased these activities. In addition, DLL3 positively regulated SNAI1 expression and knockdown of SNAI1 attenuated the migration and invasion ability of SCLC cells. Moreover, upregulated DLL3 expression induced subcutaneous tumor growth in mouse models. These results indicate that DLL3 promoted tumor growth, migration and invasion in an SCLC model by modulating SNAI1/Snail.

SUBMITTER: Furuta M

PROVIDER: S-EPMC6501010 | biostudies-literature | 2019 May

REPOSITORIES: biostudies-literature

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DLL3 regulates the migration and invasion of small cell lung cancer by modulating Snail.

Furuta Megumi M Kikuchi Hajime H Shoji Tetsuaki T Takashima Yuta Y Kikuchi Eiki E Kikuchi Junko J Kinoshita Ichiro I Dosaka-Akita Hirotoshi H Sakakibara-Konishi Jun J

Cancer science 20190413 5

Delta-like protein 3 (DLL3) is a ligand of Notch signaling, which mediates cell-fate decisions and is tumor-suppressive or oncogenic depending on the cellular context. Previous studies show that DLL3 is highly expressed in small cell lung cancer (SCLC) but not in normal lung tissue, suggesting that DLL3 might be associated with neuroendocrine tumorigenesis. However, its role in SCLC remains unclear. To investigate the role of DLL3 in tumorigenesis in SCLC, we performed loss-of-function and gain- ...[more]

PMID: 30874360

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Project description: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-?1 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-?B 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-? signal pathway in NSCLC cells rather than NF-?B 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 I?B? and NF-?B 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-? signal pathway, which subsequently inhibited migration and invasion of NSCLC cells through interfering NF-?B/Snail signal pathway in NSCLC cells.

Dataset Information

DLL3 regulates the migration and invasion of small cell lung cancer by modulating Snail.

Publications

DLL3 regulates the migration and invasion of small cell lung cancer by modulating Snail.

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