EHF enhances malignancy by modulating AKT and MAPK/ERK signaling in non-small cell lung cancer cells

Abstract

Overexpression of ETS-homologous factor (EHF) in non-small cell lung cancer (NSCLC) is associated with poor patient prognosis. To explore the mechanism of the effect of EHF in NSCLC, EHF expression was examined in NSCLC and its role in cell proliferation, invasion, cell cycle, and apoptosis of NSCLC cells was evaluated by overexpressing EHF and/or knocking down EHF expression in NSCLC cells in vitro and in cancer cell grafted mice in vivo. The results revealed that the knockdown of EHF expression in NSCLC with siRNA significantly inhibited cell proliferation and invasion, arrested the cell cycle at the G0/G1 phase, and induced apoptosis, whereas overexpression of EHF in NSCLC promoted cell proliferation, tumor growth, and cancer cell migration in vitro. The in vivo experiments demonstrated that siRNA-mediated downregulation of EHF expression in NSCLC cells significantly suppressed tumor growth in xenografted nude mice as compared to cancer progression in the mice grafted with NSCLC cells transfected with non-specific control siRNA. The biochemical analyses revealed that EHF promoted NSCLC growth by regulating the transcription of Erb-B2 receptor tyrosine kinase 2/3 (ERBB2, ERBB3) and mesenchymal-epithelial transition (MET) factor tyrosine kinase receptors and modulating the AKT and ERK signaling pathways in the NSCLC cells. The present findings indicated that EHF could be used as a prognostic marker for NSCLC, and tyrosine kinase receptors of ERBB2, ERBB3 and MET could be drug targets for NSCLC treatment.