Targeted deletion of Kcne2 causes gastritis cystica profunda and gastric neoplasia.
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.
Roepke
Torsten K
TK
Department of Pharmacology, Weill Medical College of Cornell University, New York, New York, United States of America.
Purtell
Kerry
K
King
Elizabeth C
EC
La Perle
Krista M D
KM
Lerner
Daniel J
DJ
Abbott
Geoffrey W
GW
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
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