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Gastric Cancer

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01-01-2020 | Gastritis | Original Article

A genetic origin for acid–base imbalance triggers the mitochondrial damage that explains the autoimmune response and drives to gastric neuroendocrine tumours

Authors: Javier Benítez, Roberta Marra, José Reyes, Oriol Calvete

Published in: Gastric Cancer | Issue 1/2020

Abstract

Background

Type I gastric neuroendocrine tumors (gNETs) arise from hypergastrinemia in patients with autoimmune chronic atrophic gastritis. According to the classical model, the gastric H+/K+ ATPase was the causative autoantigen recognized by CD4+ T cells in chronic autoimmune scenario that secretes IL-17 and correlates with parietal cell (PC) atrophy, which drives to gastric achlorhydria and increases the risk for gastric neoplasms. However, the mechanism by which the inflammatory response correlates with PC atrophy is not clearly defined.

Methods

Recently, we found that the ATP4A^p.R703C mutation impaired PC function and gastric acidification, which drove familial gNET. Our group constructed a knock-in mouse model for the ATP4A mutation, which has served us to better understand the relation between impaired capability to export protons across the plasma membrane of PCs and tumor progression.

Results

The ATP4A^p.R703C mutation drives gastric achlorhydria, but also deregulates the acid–base balance within PCs, affecting mitochondrial biogenesis. Mitochondrial malfunction activates ROS signaling, which triggers caspase-3-mediated apoptosis of parietal cells. In addition, when gastric euchlorhydria was restored, mitochondrial function is recovered. Infection by H. pylori promotes destabilization of the mitochondria of the PCs by a mechanism similar to that described for APT4A^p.R703C carriers.

Conclusions

A genetic origin that drives mitochondria alteration would initiate the gastric chronic inflammation instead of the classical IL-17 secretion-mediated mechanism explanation. Gastric euchlorhydria restoration is suggested to be indicated for mitochondrial recover. Our results open a new window to understand gastric neoplasms formation but also the inflammatory mechanisms and autoimmune disorders conducted by genetic origin that composes a premalignant scenario.

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Title: A genetic origin for acid–base imbalance triggers the mitochondrial damage that explains the autoimmune response and drives to gastric neuroendocrine tumours
Authors: Javier Benítez
Roberta Marra
José Reyes
Oriol Calvete
Publication date: 01-01-2020
Publisher: Springer Singapore
Keyword: Gastritis
Published in: Gastric Cancer / Issue 1/2020
Print ISSN: 1436-3291
Electronic ISSN: 1436-3305
DOI: https://doi.org/10.1007/s10120-019-00982-4

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