Basic Study
Copyright ©The Author(s) 2019. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Jan 21, 2019; 25(3): 330-345
Published online Jan 21, 2019. doi: 10.3748/wjg.v25.i3.330
NKX6.3 protects against gastric mucosal atrophy by downregulating β-amyloid production
Jung Hwan Yoon, Yeon Soo Lee, Olga Kim, Hassan Ashktorab, Duane T Smoot, Suk Woo Nam, Won Sang Park
Jung Hwan Yoon, Olga Kim, Suk Woo Nam, Won Sang Park, Department of Pathology, College of Medicine, The Catholic University of Korea, Seoul 06591, South Korea
Jung Hwan Yoon, Suk Woo Nam, Won Sang Park, Functional RNomics Research Center, College of Medicine, The Catholic University of Korea, Seoul 06591, South Korea
Yeon Soo Lee, Department of Hospital Pathology, College of Medicine, The Catholic University of Korea, Seoul 06591, South Korea
Hassan Ashktorab, Department of Medicine, Howard University, Washington, DC 20060, United States
Duane T Smoot, Department of Medicine, Meharry Medical Center, Nashville, TN 37208, United States
Author contributions: Yoon JH performed the majority of experiments, analyzed and interpreted the data, acquired funding and contributed to manuscript writing; Lee YS and Kim O reviewed and edited the manuscript; Ashktorab H and Smoot DT provided HFE-145 cells; Nam SW reviewed and edited the manuscript and helped in data interpretation; Park WS conceived the project, interpreted the data, acquired funding and wrote the manuscript.
Supported by the Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education, Science and Technology, No. 2018R1A2A2A14019713 to Park WS.
Institutional review board statement: The study was approved by the Institutional Review Board of The Catholic University of Korea, College of Medicine (MC16SISI0130).
Conflict-of-interest statement: The authors disclose no potential conflicts of interest.
Data sharing statement: No data are available.
Open-Access: This is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Corresponding author: Won Sang Park, MD, PhD, Doctor, Professor, Department of Pathology, College of Medicine, The Catholic University of Korea, 222 Banpo-daero, Seocho-gu, Seoul 06591, South Korea. wonsang@catholic.ac.kr
Telephone: +82-2-22587310 Fax: +82-2-5376586
Received: October 18, 2018
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
Processing time: 95 Days and 22.5 Hours
ARTICLE HIGHLIGHTS
Research background

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.

Research motivation

A better understanding of molecular mechanism underlying gastric mucosal atrophy could protect against gastric mucosal atrophy and gastric carcinogenesis.

Research objectives

To investigate whether NKX6.3 might play a critical role in the development of gastric mucosal atrophy by regulating Aβ production.

Research methods

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.

Research results

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.

Research conclusions

These data strongly suggest that NKX6.3 inhibit gastric mucosal atrophy by regulating Aβ accumulation and inflammatory reaction in gastric epithelial cells.

Research perspectives

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.