Abstract
Gastric cancer is the second leading cause of cancer death worldwide. Predisposing factors include achlorhydria, Helicobacter pylori infection, oxyntic atrophy and TFF2-expressing metaplasia. In parietal cells, apical potassium channels comprising the KCNQ1 α subunit and the KCNE2 β subunit provide a K+ efflux current to facilitate gastric acid secretion by the apical H+K+ATPase. Accordingly, genetic deletion of murine Kcnq1 or Kcne2 impairs gastric acid secretion. Other evidence has suggested a role for KCNE2 in human gastric cancer cell proliferation, independent of its role in gastric acidification. Here, we demonstrate that 1-year-old Kcne2 −/− mice in a pathogen-free environment all exhibit a severe gastric preneoplastic phenotype comprising gastritis cystica profunda, 6-fold increased stomach mass, increased Ki67 and nuclear Cyclin D1 expression, and TFF2- and cytokeratin 7-expressing metaplasia. Some Kcne2 −/−mice also exhibited pyloric polypoid adenomas extending into the duodenum, and neoplastic invasion of thin walled vessels in the sub-mucosa. Finally, analysis of human gastric cancer tissue indicated reduced parietal cell KCNE2 expression. Together with previous findings, the results suggest KCNE2 disruption as a possible risk factor for gastric neoplasia.
Highlights
Gastric cancer remains one of the major causes of mortality, and the second leading cause of cancer death, worldwide
KCNE2-KCNQ1 channels are considered essential for gastric acid secretion and thought to provide luminal K+ ions as a substrate for the gastric HKA
Kcne22/2 mice exhibit progressive gastric hyperplasia We previously demonstrated that Kcne2 is required for normal regulation of gastric mucosal cell growth: 3-month-old Kcne22/2 mice have gastric hyperplasia, achlorhydria and abnormal parietal cell morphology [7]
Summary
Gastric cancer remains one of the major causes of mortality, and the second leading cause of cancer death, worldwide. Parietal cells achieve gastric acidification by virtue of an apical H+K+ATPase (HKA) which pumps protons into the stomach lumen in exchange for K+ ions. To maintain this activity, K+ ions must travel from the parietal cell into the stomach lumen via the apical membrane, to ensure continued substrate for the HKA [2]. K+ ions must travel from the parietal cell into the stomach lumen via the apical membrane, to ensure continued substrate for the HKA [2] This K+ ion efflux occurs through one or more types of apical, K+selective channels. KCNE2-KCNQ1 channels are considered essential for gastric acid secretion and thought to provide luminal K+ ions as a substrate for the gastric HKA
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