Abstract
The transmembrane and secreted protein delta-like 1 homolog (DLK1) belongs to the EGF-like family. It is widely accepted that DLK1 plays important roles in regulating cell differentiation, such as adipogenesis and osteogenesis. Aberrant expression of DLK1 has been found in various types of human cancers, including lung cancer. A previous study in this lab has revealed that DLK1 is associated with tumor invasion, although the mechanism is still unknown. To explore the potential effects that DLK1 might have on invasion, DLK1 was overexpressed or knocked down in the human lung cancer cell lines. The protein's influences on cell invasion were subsequently evaluated. A transwell assay showed that DLK1 overexpression significantly promoted cancer cell invasion. Western blotting and gelatin zymography analysis indicated that DLK1 could affect both matrix metalloproteinase-9 (MMP9) expression and its extracellular activity. An analysis of NOTCH1 and HES1 gene expression and Notch intracellular domain (NICD) nuclear translocation during DLK1 stimulation or depletion demonstrated that DLK1 could activate Notch signaling in lung cancer cells. Additionally, the elevated expression of MMP9 induced by DLK1 stimulation could be significantly decreased by inhibiting Notch signaling using γ-secretase inhibitor (GSI). The data presented in this study suggest that DLK1 can promote the invasion of lung cancer cells by upregulating MMP9 expression, which depends on Notch signaling.
Highlights
Lung cancer is the leading cause of cancer death worldwide, and tumor metastasis is strongly associated with the prognosis of cancer patients [1,2]
Our previous work on metastasis-associated genes in human lung squamous cell carcinoma (SCC) suggested that delta-like 1 homolog (DLK1) might function in tumor metastasis
We validated that overexpression of DLK1 could enhance the invasive ability of lung cancer cells, which is consistent with our earlier findings derived from gene expression profiling and extends our knowledge of dlk1’s function in human cancer
Summary
Lung cancer is the leading cause of cancer death worldwide, and tumor metastasis is strongly associated with the prognosis of cancer patients [1,2]. Our previous studies on differentially expressed genes in human lung squamous cell carcinoma (SCC) with or without lymph node metastasis using DNA microarray analysis found a set of metastasis-associated genes (fdr,0.05, data not shown). Among those genes, DLK1 showed more than two-fold higher expression in primary tumors with lymph node metastasis, suggesting that DLK1 may play roles in cancer metastasis. The delta-like 1 homolog (DLK1) gene, with the aliases FA1, ZOG and PREF-1, encodes a transmembrane and secreted protein (DLK1) containing six epidermal growth factor (EGF) domains that is a member of the EGF-like family This protein is highly homologous to the Notch ligand DLL1 but lacks the Delta/ Serrate/Lag (DSL) motif that is critical for interacting with Notch receptors [3,4]. Upregulated expression of DLK1 in non-small cell lung cancer is associated with lymph node metastasis, but the mechanism is still unknown
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