Abstract
Gastric cancer (GC) after eradication for Helicobacter pylori (H.pylori) increases, but its carcinogenesis is not elucidated. It is mainly found in acid non-secretion areas (ANA), as mucosal regeneration in acid secretory areas (AA) after eradication changes the acidity and bile toxicity of gastric juice. We aimed to clarify the role of barrier dysfunction of ANA by the stimulation of pH3 bile acid cocktail (ABC) during carcinogenesis. We collected 18 patients after curative endoscopic resection for GC, identified later than 24 months after eradication, and took biopsies by Congo-red chromoendoscopy to distinguish AA and ANA (UMIN00018967). The mucosal barrier function was investigated using a mini-Ussing chamber system and molecular biological methods. The reduction in mucosal impedance in ANA after stimulation was significantly larger than that in AA, 79.6% vs. 87.9%, respectively. The decrease of zonula occludens-1 (ZO-1) and let-7a and the increase of snail in ANA were significant compared to those in AA. In an in vitro study, the restoration of ZO-1 and let-7a as well as the induction of snail were observed after stimulation. High mobility group A2 (HMGA2)-snail activation, MTT proliferation, and cellular infiltration capacity were significantly increased in AGS transfected with let-7a inhibitor, and vice versa. Accordingly, using a mini-Ussing chamber system for human biopsy specimens followed by an in vitro study, we demonstrated for the first time that the exposure of acidic bile salts to ANA might cause serious barrier dysfunction through the let-7a reduction, promoting epithelial-mesenchymal transition during inflammation-associated carcinogenesis even after eradication.
Highlights
Prevalence and mortality rates of gastric cancer (GC) remain high throughout the world
Using a mini-Ussing chamber system for human biopsy specimens followed by an in vitro study, we demonstrated for the first time that the exposure of acidic bile salts to acid non-secretion areas (ANA) might cause serious barrier dysfunction through the let-7a reduction, promoting epithelial-mesenchymal transition during inflammationassociated carcinogenesis even after eradication
Most of the macroscopic findings of post-eradication Gastric cancer (GC) were the depressed type with a tumor diameter of 12.5 (13.9 S.D.) mm, and the majority of their pathological findings were well-moderately differentiated adenocarcinoma limited to the mucosal layer, classified as T1N0M0 [16]
Summary
Prevalence and mortality rates of gastric cancer (GC) remain high throughout the world. Previous studies investigated the histological changes using the updated Sydney system more than 10 years after eradication, and demonstrated that, active inflammation was rarely seen within 1 year, chronic inflammation, atrophy, and intestinal metaplasia had persisted for a long time [6]. Another www.oncotarget.com study revealed that the numbers of methylated oncogenic genes increased significantly in the gastric tissue with chronic inflammation [7]. These suggested that chronic inflammation persisting even after successful eradication might play a major role in the development of gastric carcinogenesis [3]
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