Acidic bile salts induces mucosal barrier dysfunction through let-7a reduction during gastric carcinogenesis after Helicobacter pylori eradication

Yasushi Takahashi, Kaname Uno, Katsunori Iijima, Yasuhiko Abe, Tomoyuki Koike, Naoki Asano, Kiyotaka Asanuma, Toru Shimosegawa

研究成果: Article査読

3 被引用数 (Scopus)

抄録

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 inflammationassociated carcinogenesis even after eradication.

本文言語English
ページ(範囲)18069-18083
ページ数15
ジャーナルOncotarget
9
26
DOI
出版ステータスPublished - 2018 4 1

ASJC Scopus subject areas

  • 腫瘍学

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