NKX6.3 protects against gastric mucosal atrophy by downregulating β-amyloid production
| Autor: | Jung Hwan Yoon, Yeon Soo Lee, Won Sang Park, Suk Woo Nam, Hassan Ashktorab, Duane T. Smoot, Olga Kim |
|---|---|
| Rok vydání: | 2019 |
| Předmět: |
Gastritis
Atrophic Apolipoprotein E Carcinogenesis Atrophic gastritis Down-Regulation Cell Line Helicobacter Infections Proinflammatory cytokine 03 medical and health sciences 0302 clinical medicine NKX6.3 Bacterial Proteins Western blot Gastrectomy Stomach Neoplasms medicine Gastric mucosa Amyloid precursor protein Humans Viability assay RNA Small Interfering Homeodomain Proteins Antigens Bacterial Amyloid beta-Peptides Helicobacter pylori medicine.diagnostic_test biology Chemistry Gastroenterology Epithelial Cells Amyloid β General Medicine Basic Study medicine.disease Gastrokine 1 Molecular biology Real-time polymerase chain reaction medicine.anatomical_structure 030220 oncology & carcinogenesis biology.protein 030211 gastroenterology & hepatology Atrophy Precancerous Conditions Transcription Factors |
| Zdroj: | World Journal of Gastroenterology |
| ISSN: | 1007-9327 |
| DOI: | 10.3748/wjg.v25.i3.330 |
| Popis: | 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 β (Aβ) production. AIM To determine whether NKX6.3 might protect against gastric mucosal atrophy by regulating Aβ production. METHODS 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. 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-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. CONCLUSION NKX6.3 inhibits gastric mucosal atrophy by regulating Aβ accumulation and inflammatory reaction in gastric epithelial cells. |
| Databáze: | OpenAIRE |
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