Helicobacter pylori (H. pylori) is a risk factor of gastric carcinoma, and inflammation with H.pylori infection has widely been suggested to trigger gastric carcinogenesis through "inflammation-carcinoma chain" (non-atrophic gastritis (NAG) → chronic atrophic gastritis (CAG) → intestinal metaplasia (IM) → dysplasia (DYS) and gastric carcinoma (GC)). Connexin43 (Cx43) is a major constituent of gap junction in normal gastric mucosa (NGM) and it is continuously down-regulated from normal gastric mucosa to precancerous lesions or ultimate gastric carcinoma, which shows novel target against gastric carcinoma by preventing the Cx43 decline. Our previous studies demonstrated that H. pylori infection in gastric mucosa down-regulates Cx43 expression, but its mechanism remains unknown. The transcriptional factor, GATA binding protein 3 (GATA-3) is the key to regulate adaptive immune response, which possibly relates to inflammation toward malignant transformation. Here the substantial rising of GATA-3 was screened by transcriptional factor microarray along the developmental stages of H. pylori associated gastric carcinoma. Moreover, the increased GATA-3 and inhibited Cx43 were confirmed in clinical specimens, Mongolian gerbils and normal gastric epithelial cell line GES-1 with H. pylori infection. GATA-3 silencing generated the Cx43 restoration both in intermediate differentiation gastric cancer cells BGC-803 and in H. pylori infected GES-1 cells. Dual-luciferase reporter assay further revealed the GATA-3 as one of Cx43 down-regulators by directly binding to its promoters. Together, the incremental GATA-3 is found in H. pylori associated gastric carcinogenesis, which is responsible for Cx43 inhibition as well.
Keywords: CAG, chronic atrophic gastritis; CagA, cytotoxin-associated gene A; Connexin43; Cx43, connexin43; DYS, dysplasia; GATA-3; GATA-3, GATA binding protein 3; GC, gastric carcinoma; GJ, gap junction; H. pylori, Helicobacter pylori; Helicobacter pylori; IFN-γ, interferon-gamma; ILC, innate lymphoid cell; IM, intestinal metaplasia; NAG, non-atrophic gastritis; NGM, normal gastric mucosa.; PBMC, peripheral blood mononuclear cell; PBS, phosphate buffered saline; TF, transcriptional factor; Th1/Th2 cell, type 1/2 T helper cell; VacA, vacuolating cytotoxin gene A; carcinogenesis; gastric carcinoma; inflammation-carcinoma chain; transcription factor.