Heightened susceptibility to chronic gastritis, hyperplasia and metaplasia in Kcnq1 mutant mice

Abstract

Increased susceptibility to gastric cancer has been associated with a wide range of host genetic and environmental factors, including Helicobacter pylori infection. Helicobacter pylori infection is postulated to initiate a progression through atrophic gastritis, metaplasia and dysplasia to cancer, and has been associated with reduction of acid output and dysregulation of stomach mucins. Here, we present the characterization of two mouse lines carrying mutant alleles of the gene encoding the Kcnq1 potassium channel, which very rapidly establish chronic gastritis in a pathogen-exposed environment. These mice develop gastric hyperplasia, hypochlorhydria and mucin dysregulation independent of infection. Metaplasia, dysplasia and pre-malignant adenomatous hyperplasia of the stomach have been observed in these Kcnq1 mutant mice, also independent of infection. The data presented here suggest that Kcnq1 mutant mice can be used both as an efficient model for the development of atrophic gastritis after infection and to determine the processes during the later stages of progression to gastric cancer independent of infection. Thus, Kcnq1 mutant mice are a powerful new tool for investigating the connection between acid balance, Helicobacter infection and mucin disruption in the progression to gastric cancer.

Interferon gamma induction of gastric mucous neck cell hypertrophy

“…Both of these models exhibit a mucous cell lineage morphologically similar to SPEM and similar to the expanded mucous neck cell compartment we observed in the GÀ/À mice. 8,12 There are three possible mechanisms by which the mucous neck cell compartment may expand. Two of these mechanisms were observed in the models examined in this study.…”

“…6 Emergence of a prominent mucous cell lineage (the so-called 'mucous cell metaplasia') was found to be one of the earliest histological changes in the fundic mucosa of these mice. 5 Mucosal changes bearing similar features have also been reported in a variety of pathological processes in human and mouse, which include H. pylori infection; [7][8][9] loss of parietal cells upon chemical administration; 10 treatment with a carcinogen, 11 mutation of the Kcnq1 gene encoding a potassium channel, 12 and constitutively active STAT3. 13 This type of mucosal change may therefore represent a common, and possibly reversible 10 response of the stomach, to mucosal injury and tissue inflammation triggered by various stimuli.…”

Phenotypic Analysis of Vertigo 2 Jackson Mice with a Kcnq1 Potassium Channel Mutation

“…Molecular characterization of this strain has revealed transcripts lacking exon 1α through exon 2, which would potentially encode a protein missing the first transmembrane domain of the ion channel [9]. In the present study, we analyzed the various phenotypic characteristics of vtg-2J mice, and examined the possible usefulness of this strain for studying the physiological functions of Kcnq1.…”

“…Kcnq1 mutant mice display deafness [5,10,12], which is most likely due to the essential role of the Kcnq1-encoded channel in generating high potassium concentrations in the endolymph. Kcnq1 is also known to be essential for gastric acid secretion [11], and gastric hyperplasia has been reported in Kcnq1 mutant animals [9,10,12].…”

KCNE2 and the K+channel

“…Both components of this channel are essential: targeted deletion of either Kcnq1 or Kcne2 causes achlorhydria and increased gastric mass arising from mucus neck cell hyperplasia. [33][34][35][36] KCNE3 is also detectable in the stomach, and appears to be expressed at relatively low levels in parietal cells, but is more readily detected in other gastric cells, possibly mucus neck cells and/or guard cells. 18,37 However, Kcne3 2/2 mice do not exhibit gastric hyperplasia, achlorhydria, or any other obvious gastric phenotype, indicating KCNE3 is not required for gastric acid secretion.…”