Disruption of Klf4 in Villin-Positive Gastric Progenitor Cells Promotes Formation and Progression of Tumors of the Antrum in Mice

Abstract

Krüppel-like factor 4 (Klf4) is a putative gastric tumor suppressor gene. Rare, villin-positive progenitor cells in the gastric antrum have multilineage potential. We investigated the function of Klf4 in these cells and in gastric carcinogenesis. We created mice with disruption of Klf4 in villin-positive antral mucosa cells (Villin-Cre(+);Klf4(fl/fl) mice). Villin-Cre(+);Klf4(fl/fl) and control mice were given drinking water with or without 240 ppm N-methyl-N-nitrosourea at 5 weeks of age and thereafter on alternating weeks for a total of 10 weeks. Gastric mucosa samples were collected at 35, 50, or 80 weeks of age from mice that were and were not given N-methyl-N-nitrosourea, and analyzed by histopathologic and molecular analyses. Findings were compared with those from human gastric tumor specimens. Preneoplasia formed progressively in the antrum in 35- to 80-week-old Villin-Cre(+);Klf4(fl/fl) mice. Gastric tumors developed in 29% of 80-week-old Villin-Cre(+);Klf4(fl/fl) mice, which were located exclusively in the lesser curvature of the antrum. N-methyl-N-nitrosourea accelerated tumor formation, and tumors developed significantly more frequently in Villin-Cre(+);Klf4(fl/fl) mice than in control mice, at 35 and 50 weeks of age. Mouse and human gastric tumors had reduced expression of Krüppel-like factor 4 and increased expression of FoxM1 compared with healthy gastric tissue. Expression of Krüppel-like factor 4 suppressed transcription of FoxM1. Inactivation of Klf4 in villin-positive gastric progenitor cells induces transformation of the gastric mucosa and tumorigenesis in the antrum in mice. Villin-Cre(+);Klf4(fl/fl) have greater susceptibility to chemical-induced gastric carcinogenesis and increased rates of gastric tumor progression than control mice.