Published online Jan 21, 2019. doi: 10.3748/wjg.v25.i3.330
Peer-review started: October 18, 2018
First decision: November 29, 2018
Revised: December 21, 2018
Accepted: December 21, 2018
Article in press: December 21, 2018
Published online: January 21, 2019
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 β (Aβ) production.
To determine whether NKX6.3 might protect against gastric mucosal atrophy by regulating Aβ production.
We identified NKX6.3 depletion induced cell death by cell count and Western blot assay. Production and mechanism of Aβ 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, Helicobacter pylori CagA, Aβ oligomer, apolipoprotein E (ApoE), and β-secretase 1 (Bace1) in 55 gastric mucosae.
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-145shNKX6.3 cells. NKX6.3 depletion produced Aβ peptide oligomers, and increased expression of ApoE, amyloid precursor protein, Aβ, Bace1, low-density lipoprotein receptor, nicastrin, high mobility group box1, and receptor for advanced glycosylation end product proteins. In immunoprecipitation assay, γ-secretase complex was stably formed only in HFE-145shNKX6.3 cells. In gastric mucosae with atrophy, expression of Aβ peptide oligomer, ApoE, and Bace1 was detected and inversely correlated with NKX6.3 expression. Treatment with recombinant Aβ 1-42 produced Aβ oligomeric forms and decreased cell viability in HFE-145shNKX6.3 cells. Additionally, NKX6.3 depletion increased expression of inflammatory cytokines and cyclooxygenase-2.
NKX6.3 inhibits gastric mucosal atrophy by regulating Aβ accumulation and inflammatory reaction in gastric epithelial cells.
Core tip: In human gastric epithelial cells, NKX6.3 depletion induced production of amyloid β (Aβ) oligomers, and also increased expression of apolipoprotein E (ApoE), Aβ, β-secretase 1 (Bace1), nicastrin, and receptor for advanced glycosylation end product proteins. Moreover, NKX6.3 depletion leads to stably formed of γ-secretase complex and binding to Bace1 protein. In gastric mucosae with atrophy, expression of Aβ oligomer, ApoE, and Bace1 was detected and inversely correlated with NKX6.3 expression. Additionally, treatment with recombinant Aβ 1-42 produced oligomeric forms of Aβ and significantly decreased cell viability in NKX6.3 depleting cells. These observations provide evidences that NKX6.3 can inhibit gastric mucosal atrophy by regulating Aβ peptide accumulation and inflammatory reaction in gastric epithelial cells.