title: Targeted deletion of Kcne2 causes gastritis cystica profunda and gastric neoplasia.
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 alpha subunit and the KCNE2 beta 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.
authors.affiliation: Department of Pharmacology, Weill Medical College of Cornell University, New York, New York, United States of America.
authors.forename: Torsten K
authors.initials: TK
authors.lastname: Roepke
authors.forename: Kerry
authors.initials: K
authors.lastname: Purtell
authors.forename: Elizabeth C
authors.initials: EC
authors.lastname: King
authors.forename: Krista M D
authors.initials: KM
authors.lastname: La Perle
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Lerner
authors.forename: Geoffrey W
authors.initials: GW
authors.lastname: Abbott
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002460:Cell Line; D045744:Cell Line, Tumor; D019938:Cyclin D1 / Q000235:genetics / Q000378:metabolism; D005455:Fluorescent Antibody Technique; D005753:Gastric Mucosa / Q000378:metabolism / Q000473:pathology; D005756:Gastritis / Q000209:etiology* / Q000235:genetics*; D017353:Gene Deletion; D017506:H(+)-K(+)-Exchanging ATPase / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D051657:KCNQ1 Potassium Channel / Q000235:genetics / Q000378:metabolism; D019394:Ki-67 Antigen / Q000235:genetics / Q000378:metabolism; D008679:Metaplasia / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008817:Mice, Mutant Strains; D010455:Peptides / Q000235:genetics / Q000378:metabolism; D024642:Potassium Channels, Voltage-Gated / Q000235:genetics / Q000378:metabolism*; D013274:Stomach Neoplasms / Q000209:etiology* / Q000235:genetics*; D000071164:Trefoil Factor-2
chemical_list: C489619:KCNE2 protein, human; D051657:KCNQ1 Potassium Channel; C496909:KCNQ1 protein, human; D019394:Ki-67 Antigen; D010455:Peptides; D024642:Potassium Channels, Voltage-Gated; C000604007:TFF2 protein, human; D000071164:Trefoil Factor-2; D019938:Cyclin D1; D017506:H(+)-K(+)-Exchanging ATPase