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

Abstract

BACKGROUND & AIMS:

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.

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 Krüppel-like factor 4 and increased expression of FoxM1 compared with healthy gastric tissue. Expression of Krüppel-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.

• Authors: Qiang Li, Zhiliang Jia, Li Wang, Xiangyu Kong, Qi Li, Kun Guo, Dongfeng Tan, Xiangdong Le, Daoyan Wei, Suyun Huang, Lopa Mishra, Keping Xie
• Journal: Gastroenterology (Gastroenterology) Vol. 142 Issue 3 Pg. 531-42 (Mar 2012) ISSN: 1528-0012 [Electronic] United States
• PMID: 22155367 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2012 AGA Institute. Published by Elsevier Inc. All rights reserved.

Chemical References

• FOXM1 protein, human
• Forkhead Box Protein M1
• Forkhead Transcription Factors
• Foxm1 protein, mouse
• KLF4 protein, human
• Klf4 protein, mouse
• Kruppel-Like Factor 4
• Kruppel-Like Transcription Factors
• Microfilament Proteins
• villin
• Methylnitrosourea
• Cre recombinase
• Integrases

Topics

• Animals
• Cell Line, Tumor
• Cell Transformation, Neoplastic (genetics, metabolism, pathology)
• Forkhead Box Protein M1
• Forkhead Transcription Factors (metabolism)
• Gastric Mucosa (metabolism, pathology)
• Genotype
• Humans
• Integrases (genetics, metabolism)
• Kruppel-Like Factor 4
• Kruppel-Like Transcription Factors (deficiency, genetics, metabolism)
• Methylnitrosourea
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Mice, Transgenic
• Microfilament Proteins (genetics)
• Neoplastic Stem Cells (metabolism, pathology)
• Phenotype
• Precancerous Conditions (chemically induced, genetics, metabolism, pathology)
• Promoter Regions, Genetic
• Pyloric Antrum (metabolism, pathology)
• Stomach Neoplasms (chemically induced, genetics, metabolism, pathology)
• Time Factors