RRC ID 54542
Author Echizen K, Horiuchi K, Aoki Y, Yamada Y, Minamoto T, Oshima H, Oshima M.
Title NF-κB-induced NOX1 activation promotes gastric tumorigenesis through the expansion of SOX2-positive epithelial cells.
Journal Oncogene
Abstract We previously showed that NADPH oxidase organizer 1 (Noxo1), a component of NADPH oxidase 1 (NOX1), is a TNF-α-induced tumor-promoting factor in gastric tumorigenesis. However, the mechanism of NOX1-induced reactive oxygen species (ROS) signaling for the gastric tumorigenesis has not been understood. Here, we showed that expression of NOX1 complex components, including Noxo1, but not other NOX family members was significantly upregulated in both mouse models for gastritis and gastric tumors, which was associated with increased ROS levels. We also found that NF-κB directly regulated NOXO1 expression in TNF-α-stimulated gastric cancer cells, suggesting that inflammation induces NOX1 complex activation through TNF-α/NF-κB pathway. Notably, in situ hybridization indicated that Noxo1 mRNA was detected in proliferating cells of gastritis and gastric tumors, and pharmacological inhibition of NOX activity significantly suppressed the proliferation of MKN45 gastric cancer cells and gastric hyperplasia of K19-C2mE mice. These results suggest that NOX1/ROS signaling has an important role in increased proliferation of stomach epithelial cells in the inflamed mucosa. Moreover, we found that expression of SOX2, a marker of gastric epithelial stem cells, was increased by NOX1/ROS signaling. Furthermore, disruption of Noxo1 in K19-C2mE mice significantly suppressed gastritis-associated metaplastic hyperplasia, a potent preneoplastic lesion, which was associated with decreased number of SOX2-positive cells. These results indicate that inflammation-induced Noxo1 expression is responsible for development of metaplastic hyperplasia in the stomach through an increase in SOX2-expressing undifferentiated epithelial cells. Therefore, inhibition of the NOX1/ROS signaling pathway is a possible strategy for prevention and therapy for gastric cancer development.
Volume 38(22)
Pages 4250-4263
Published 2019-5-1
DOI 10.1038/s41388-019-0702-0
PII 10.1038/s41388-019-0702-0
PMID 30700829
PMC PMC6756228
MeSH Animals Carcinogenesis / metabolism* Carcinogenesis / pathology Cell Line, Tumor Cell Proliferation / physiology Epithelial Cells / metabolism* Epithelial Cells / pathology Gene Expression Regulation / physiology Humans Inflammation / metabolism Inflammation / pathology Mice Mice, Inbred C57BL NADPH Oxidase 1 / metabolism* NF-kappa B / metabolism* Reactive Oxygen Species / metabolism SOXB1 Transcription Factors / metabolism* Signal Transduction / physiology Stomach / pathology* Stomach Neoplasms / metabolism* Stomach Neoplasms / pathology Tumor Necrosis Factor-alpha / metabolism
IF 6.634
Times Cited 7
DNA material CS-RfA-CG (RDB04390) pCMV-VSV-G-RSV-Rev (RDB04393) pCAG-HIVgp (RDB04394)
Human and Animal Cells Kato III(RCB2088) MKN45(RCB1001)