Abstract
NKX6.3 plays an important role in gastric epithelial differentiation and also acts as a gastric tumor suppressor. The specific aim of this study was to determine whether NKX6.3 contributes to gastric mucosal barrier function by regulating reactive oxygen species (ROS) production. NKX6.3 reduced ROS production and regulated expression of anti-oxidant genes, including Hace1. In addition, NKX6.3 reduced DNMT1 expression and activity by down-regulating NF-kB family gene transcription. Silencing of Hace1 recovered ROS production, whereas knock-down of DNMT1 and NF-kB reduced ROS production and induced Hace1 expression by hypomethylating its promoter region. In addition, NKX6.3 inhibited CagA effects on cell growth, ROS production, and NF-kB and DNMT1 activity. In gastric mucosae and cancers, NKX6.3 and Hace1 expression was significantly reduced. The NKX6.3 expression was positively correlated with Hace1 and Nrf2 genes, but negatively correlated with DNMT1. Hypermethylation of Hace1 gene was observed only in gastric mucosae with H. pylori, atrophy and intestinal metaplasia. Thus, these results suggest that NKX6.3 inhibits ROS production by inducing the expression of Hace1 via down-regulating NF-kB and DNMT1 activity in gastric epithelial cells.
Highlights
We and others have reported that the novel transcription factor, NKX6.312, is a key factor for gastric differentiation and prevention of intestinal metaplasia and acts as a tumor suppressor for gastric cancer[13,14,15,16]
Gastric cancers develop as a consequence of chronic inflammation from persistent mucosal or epithelial cell colonization by microorganisms, including H. pylori[20]
Chronic inflammatory cells such as macrophages/monocytes, lymphocytes, and plasma cells are present in the gastric mucosa of chronic gastritis and lead to the generation of several reactive oxygen species (ROS) and RNS21
Summary
We and others have reported that the novel transcription factor, NKX6.312, is a key factor for gastric differentiation and prevention of intestinal metaplasia and acts as a tumor suppressor for gastric cancer[13,14,15,16]. ROS is reportedly involved in the development of precancerous gastritis and gastric cancer, we hypothesized that NKX6.3 may protect the gastric mucosal epithelia from harmful ROS. NKX6.3, Hace[1], Nrf[2], and DNMT1 was compared between non-neoplastic gastric mucosae and gastric cancers. We found that NKX6.3 significantly decreased ROS production and regulated the expression of ROS-related genes, including Hace[1], by suppressing DNMT1 and NF-kB activity. These results suggest that NKX6.3 plays an important role in gastric epithelial protection and gastric cancer prevention by regulating the ROS levels
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