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Accession IconGSE44617

Nicotinic acetylcholine receptors and EGF induce c-Kit ligand/Stem Cell Factor (SCF) in a -arrestin-1 and E2F1 dependent manner in NSCLC

Organism Icon Homo sapiens
Sample Icon 4 Downloadable Samples
Technology Badge Icon Affymetrix Human Genome U133 Plus 2.0 Array (hgu133plus2)

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Description
Lung cancer remains the leading cause of cancer-related deaths worldwide. -arrestin-1 (ARRB1), a scaffolding protein involved in the termination or desensitization of signals arising from activated G-protein-coupled receptors (GPCRs) has been shown to play a role in invasion and proliferation of many cancers, including nicotine-induced proliferation of human nonsmall cell lung cancers (NSCLCs). In this study, we analyzed nicotine induced and -arrestin-1 dependent genes from the microarray data. Our analysis show that SCF (Stem cell factor) strongly differentiated smokers from non-smokers implying an important role of this gene in NSCLCs. SCF, a major cytokine is the ligand for the c-Kit proto-oncogene. Here we elucidate the molecular mechanisms by which nicotine as well as EGF induces the expression of SCF in lung adenocarcinoma cell lines A549 and H1650. ChIP assays and transient transfection experiments showed that transcription factor E2F1 can positively regulate SCF expression at the transcriptional level; depletion of E2F1 or -arrestin-1 prevented the nicotine-mediated induction of SCF. Given that the binding of SCF to c-Kit leads to activation of multiple downstream signaling pathways including Src, PI3K, MEK and EGFR pathways, our data suggest that the SCF plays a central role in lung carcinogenesis, and may be a potential therapeutic target for combating NSCLC. Studies presented here also provide evidence that SCF along with nicotine promotes self-renewal and proliferation of lung cancer stem cells (CSCs). Our findings reveal an important role and prognostic significance of SCF that can serve as a novel prognostic and predictive biomarker for NSCLC.
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