Research Papers:

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 and Tooru Shimosegawa

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Oncotarget. 2018; 9:18069-18083. https://doi.org/10.18632/oncotarget.24725

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Yasushi Takahashi1, Kaname Uno1, Katsunori Iijima2, Yasuhiko Abe3, Tomoyuki Koike1, Naoki Asano1, Kiyotaka Asanuma1 and Tooru Shimosegawa1

1Division of Gastroenterology, Tohoku University, Miyagi, Japan

2Department of Gastroenterology, Akita University, Miyagi, Japan

3Department of The Second Internal Medicine, Yamagata University, Miyagi, Japan

Correspondence to:

Kaname Uno, email: [email protected]

Keywords: gastric cancer; helicobacter pylori eradication; mucosal barrier dysfunction; epithelial-mesenchymal transition

Received: October 26, 2017     Accepted: February 24, 2018     Published: April 06, 2018


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.

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