| Popis: |
Background Lung cancer is one of the leading causes of cancer-related death worldwide. Identifying alterations in oncogenic drivers are known to be an effective strategy to explore potential druggable targets in the treatment of this disease. Methods Integrative analysis of the NCBI Gene Expression Omnibus (GEO) datasets by R language identified TNFRSF21 is upregulated in lung cancers. Using overexpression or knockdown approach to demonstrate the gene effect and mechanisms on lung cancer cells. Immunohistochemical analysis of a commercial lung cancer tissue array showed clinic-pathological correlations. Results TNFRSF21 is frequently upregulated and associated with high-grade tumors and is highly correlated with advanced NSCLC. Biochemical studies confirmed that TNFRSF21 overexpression could markedly promote NSCLC cell growth and cell migration/invasion, while suppression of ERK and FOXM1 by U0126 and thiostrepton, respectively, could significantly counteract TNFRSF21-mediated NSCLC cell proliferation and aggressiveness. Mechanistic studies revealed that forced expression or ablation of TNFRSF21 could escalate or attenuate both the phosphorylation of ERK (p-ERK) and the expression of FOXM1, respectively, whereas the levels of TNFRSF21 and p-ERK were not altered when FOXM1 was inhibited by thiostrepton. On the contrary, inhibition of the intensity of p-ERK by U0126 could reduce FOXM1 expression in TNFRSF21-overexpressing NSCLC cells, which suggests that TNFRSF21 is the upstream effector of ERK signaling and that its downstream target is FOXM1. Conclusions This study highlights the significance of TNFRSF21 in promoting tumor aggressiveness in lung cancer by increasing ERK/FOXM1 signaling, which suggests that targeting TNFRSF21/MEK/ERK/FOXM1 may represent a potential therapy for lung cancer. |
