Semaphorin4A promotes lung cancer by activation of NF-κB pathway mediated by PlexinB1

Background: Lung Cancer (LC) is the most prevalent Cancer with a poor prognosis. Semaphorin4A (Sema4A) is important in many physiological and pathological processes. This study aimed to explore the role and mechanism of Sema4A in LC.

Methods: Firstly, Sema4A expression was analyzed by the available dataset and detected in human normal bronchial epithelial cell line (HBE) and LC cell line (NCI-H460). Then, LC cells were transfected with Sema4A siRNA, and the cells were stimulated by PlexinB1, PlexinB2, PlexinD1 blocking Antibodies, IgG antibody, BAY 11-7082 (an inhibitor for NF-κB pathway) and Sema4A-Fc protein, alone or in combination. After transfection, PlexinB1 mRNA expression was analyzed. Next, the biological functions, including proliferative, migratory, invasive abilities and viability of the cells were detected by colony formation, scratch, Transwell and MTT assays, respectively. NF-κB, STAT3 and MAPK protein expressions were determined by western blot. Furthermore, the secretion of IL-6 in LC cells was tested by ELISA.

Results: Sema4A was highly expressed in LC tissues and cells, could activate the NF-κB pathway and upregulate PlexinB1 mRNA expression. Furthermore, we observed that Sema4A knockdown suppressed the biological functions of NCI-H460 cells, while Sema4A-Fc protein reversed the situation. However, Sema4A-induced biological functions and activation in the NF-κB pathway were inhibited by PlexinB1 blocking antibody. Consistently, Sema4A promoted IL-6 production, which was down-regulated by PlexinB1 blocking antibody and BAY 11-7082.

Conclusions: Sema4A may facilitate LC development via the activation of the NF-κB pathway mediated by PlexinB1, suggesting that Sema4A would be a novel therapeutic target for LC treatment.

IL-6; Lung cancer; NF-κB pathway; PlexinB1; Semaphorin4A.