ATP4B suppresses cell proliferation and migration via mitochondrial/p53/NF-κB pathway in gastric cancer

Background: Hydrogen/Potassium ATPase β (ATP4B) is a key protein in gastric mucosa barrier acting an essential role in gastric acid secretion. However, the exact role and precise mechanism of ATP4B in gastric cancer (GC) remain obscure. This study aimed to investigate the clinical significance of ATP4B in GC and its biological role in tumor progression.Methods: We evaluated ATP4B expression in GC cell lines and patient specimens via qPCR and Immunofluorescence. The correlations between ATP4B expression level and clinicopathologic parameters, as well as the relevance of ATP4B expression with overall survival were assessed. The functional roles of ATP4B in GC were verified by gain- and loss-of-function cell models and xenograft tumor model. The possible downstream effects of ATP4B were analyzed by iTRAQ‑based quantitative proteomics analysis.Results: A dramatic decrease of ATP4B expression in GC cells and tissues compared with the adjacent normal tissues was observed; Downexpression of ATP4B was associated with the malignant transformation in gastric mucosa lesions and correlated with poor prognosis, high grade of TNM stage, and vessel carcinoma embolus in GC patients. Restoration of ATP4B expression in GC cells significantly inhibited cell proliferation, cell viability, migration, invasion, tumorigenicity and induced apoptosis, whereas ATP4B silencing exerted the opposite effects. Mechanistically, we found a constitutive activation of p53 and inactivation of NF-κB signaling correlated with the mitochondrial pathway in ATP4B-overexpressing GC cells.Conclusion: Our data suggest that ATP4B perform the promising tumor suppressor gene by regulating p53/NF-κB/mitochondrial pathway in GC.