Disruption of Klf4 in villin-positive gastric progenitor cells promotes formation and progression of tumors of the antrum in mice

Background & Aims: Krppel-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. Methods: 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. Results: 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 Krppel-like factor 4 and increased expression of FoxM1 compared with healthy gastric tissue. Expression of Krppel-like factor 4 suppressed transcription of FoxM1. Conclusions: 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.