MiR-22 sustains NLRP3 expression and attenuates H. pylori-induced gastric carcinogenesis

Abstract

Chronic inflammation is the primary cause of gastric cancer (GC). NLRP3, as an important inflammasome component, has crucial roles in initiating inflammation. However, the potential roles of NLRP3 in GC is unknown. Here, we show that NLRP3 expression is markedly upregulated in GC, which promotes NLRP3 inflammasome activation and interleukin-1β (IL-1β) secretion in macrophages. In addition, NLRP3 binds to cyclin-D1 (CCND1) promoter and promotes its transcription in gastric epithelial cells. Consequently, NLRP3 enhances epithelial cells proliferation and GC tumorigenesis. Furthermore, we identify miR-22, which is constitutively expressed in gastric mucosa, as a suppressor of NLRP3. MiR-22 directly targets NLRP3 and attenuates its oncogenic effects in vitro and in vivo. However, Helicobacter pylori (H. pylori) infection suppresses miR-22 expression, while enhances NLRP3 expression, and that triggers uncontrolled proliferation of epithelial cells and the emergence of GC. Thus, our research describes a mechanism by which miR-22 suppresses NLRP3 and maintains homeostasis of gastric microenvironments and suggests miR-22 as a potential target for the intervention of GC.

NOD1 mediates non-canonical inflammasome processing of interleukin-18 in epithelial cells toHelicobacter pyloriinfection

“…H. pylori upregulated IL-18 production and processing in the human AGS gastric epithelial line (Fig. 4e, f, 5d) which, contrary to previous reports 43,44 , does not appear to express either NLRP3 or ASC ( Supplementary Fig. 4 and unpublished data).…”

NOD1 mediates interleukin-18 processing in epithelial cells responding to Helicobacter pylori infection

“…H. pylori upregulated IL-18 production and processing in the human AGS gastric epithelial line (Fig. 4e, f, 5d) which, contrary to previous reports 51,52 , does not appear to express either NLRP3 or ASC (PYCARD) ( Supplementary Fig. 4).…”

The Complex Network between MYC Oncogene and microRNAs in Gastric Cancer: An Overview

“…As mentioned above, cagA enhances MYC expression, and MYC regulates EZH2 through miR-26 and miR-101 downregulation (Figure 3) [92]. The H. pylori infection also suppresses MYC-induced miR-22 expression in the gastric mucosa, and is associated with an abnormal cell proliferation [91]. miR-22 is characterized as a key regulator of the self-renewal machinery of the hematopoietic system.…”

“…This miRNA acts as a proto-oncogenic miRNA via genome-wide deregulation of the epigenetic state through the inhibition of methylcytosine dioxygenase TET2 proteins [136]. On the contrary, miR-22 is suppressed by H. pylori infection, leading to uncontrolled gastric epithelial cell proliferation and overexpression of NLRP3 (NACHT, LRR and PYD domains-containing protein 3), a gene that helps the cell to recognize pathogen-associated molecular patterns [91]. These results indicate that the environment influences the modulation of miRNAs that consequently regulate important pathways of cell proliferation.…”