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 considered as a precancerous condition of gastric cancer. However, little is known about the molecular mechanism underlying gastric mucosal atrophy. NKX6.3 plays a key role in the maintaining gastric epithelial homeostasis. Amyloid β (Aβ) acts as a neurotoxin that directly induces oxidative stress and receptor for advanced glycation end products (RAGE) mediates Aβ-induced oxidative stress and inflammatory response. Increased expression of RAGE has been implicated in the pathogenesis of neuronal cell death. Interestingly, gastrokine 1, a downstream target of NKX6.3, interacts with amyloid precursor protein (APP) and inhibits polymerization of Aβ.
A better understanding of molecular mechanism underlying gastric mucosal atrophy could protect against gastric mucosal atrophy and gastric carcinogenesis.
To investigate whether NKX6.3 might play a critical role in the development of gastric mucosal atrophy by regulating Aβ production.
We examined whether NKX6.3 depletion induces 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 in HFE-145 non-neoplastic gastric epithelial cells and gastric mucosal tissues. We further validated the correlation between expression of NKX6.3, Helicobacter pylori CagA, Aβ oligomer, apolipoprotein E (ApoE), and β-secretase 1 (Bace1) in gastric mucosae.
We found that NKX6.3 depletion increased floating cell populations in HFE-145 cells and induced production of Aβ peptide oligomers. In addition, NKX6.3 depletion increased expression of APP, Aβ, and RAGE proteins. In gastric mucosae with atrophy, expression of Aβ peptide oligomer, ApoE, and Bace1 was detected and inversely correlated with NKX6.3 expression. Treatment with rAβ 1-42 produced oligomeric forms of Aβ and significantly decreased cell viability only in HFE-145shNKX6.3 cells. Furthermore, NKX6.3 depletion in HFE-145shNKX6.3 cells increased expression of inflammatory cytokines and cyclooxygenase-2.
These data strongly suggest that NKX6.3 inhibit gastric mucosal atrophy by regulating Aβ accumulation and inflammatory reaction in gastric epithelial cells.
Additional studies are needed to validate the results obtained. Identification of molecular mechanism underlying gastric mucosal atrophy could contribute to the prevention of atrophic gastritis and gastric cancer.