NKX6.3 protects against gastric mucosal atrophy by downregulating β-amyloid production

BACKGROUND Atrophic gastritis is characterized by loss of appropriate glands and reduction in gastric secretory function due to chronic inflammatory processes in gastric mucosa. Moreover, atrophic gastritis is considered as a precancerous condition of gastric cancer. However, little is known about the molecular mechanism underlying gastric mucosal atrophy and its contribution to gastric carcinogenesis. Thus, we hypothesized that transcription factor NKX6.3 might be involved in maintaining gastric epithelial homeostasis by regulating amyloid beta (A beta) production. AIM To determine whether NKX6.3 might protect against gastric mucosal atrophy by regulating A beta production. METHODS We identified NKX6.3 depletion induced cell death by cell count and Western blot assay. Production and mechanism of A beta oligomer were analyzed by enzyme-linked immunosorbent assay, Western blot, immunoprecipitation, real-time quantitative polymerase chain reaction and immunofluorescence analysis. We further validated the correlation between expression of NKX6.3, fielicobacter pylori CagA, A beta oligomer, apolipoprotein E (ApoE), and beta-secretase 1 (Bace1) in 55 gastric mucosae. RESULTS NKX6.3 depletion increased both adherent and floating cell populations in HFE-145 cells. Expression levels of cleaved caspase-3, -9, and poly ADP ribose polymerase were elevated in floating HFE-145(shNKX6.3) cells. NKX6.3 depletion produced A beta peptide oligomers, and increased expression of ApoE, amyloid precursor protein, A beta, Bacel, low-density lipoprotein receptor, nicastrin, high mobility group box1, and receptor for advanced glycosylation end product proteins. In immunoprecipitation assay, gamma-secretase complex was stably formed only in HFE-145(shNKX6.3) cells. In gastric mucosae with atrophy, expression of A beta peptide oligomer, ApoE, and Bace1 was detected and inversely correlated with NKX6.3 expression. Treatment with recombinant A beta 1-42 produced A beta oligomeric forms and decreased cell viability in HFE-145(shNKX6.3) cells. Additionally, NKX6.3 depletion increased expression of inflammatory cytokines and cyclooxygenase-2. CONCLUSION NKX6.3 inhibits gastric mucosal atrophy by regulating A beta accumulation and inflammatory reaction in gastric epithelial cells.