Intestinal epithelial-specific PTEN inactivation results in tumor formation.

Abstract

Phosphatase and tensin homolog deleted on chromosome 10 (PTEN) is a negative regulator of phosphatidylinositol 3-kinase (PI3K) signaling that is frequently inactivated in colorectal cancer through mutation, loss of heterozygosity, or epigenetic mechanisms. The aim of this study was to determine the effect of intestinal-specific PTEN inactivation on intestinal epithelial homeostasis and tumorigenesis. PTEN was deleted specifically in the intestinal epithelium, by crossing PTEN(Lox/Lox) mice with villin(Cre) mice. PTEN was robustly expressed in the intestinal epithelium and maximally in the differentiated cell compartment. Targeted inactivation of PTEN in the intestinal epithelium of PTEN(Lox/Lox)/villin(Cre) mice was confirmed by genotyping, immunohistochemistry, and qPCR. While intestinal-specific PTEN deletion did not have a major effect on cell fate determination or proliferation in the small intestine, it did increase phosphorylated (p) protein kinase B (AKT) expression in the intestinal epithelium, and 19% of animals developed small intestinal adenomas and adenocarcinomas at 12 mo of age. These tumors demonstrated pAKT and nuclear β-catenin staining, indicating simultaneous activation of the PI3K/AKT and Wnt signaling pathways. These findings demonstrate that, while PTEN inactivation alone has a minimal effect on intestinal homeostasis, it can facilitate tumor promotion upon deregulation of β-catenin/TCF signaling, further establishing PTEN as a bona fide tumor suppressor gene in intestinal cancer.

• Authors: Do-Sun Byun, Naseem Ahmed, Shannon Nasser, Joongho Shin, Sheren Al-Obaidi, Sanjay Goel, Georgia A Corner, Andrew J Wilson, Dustin J Flanagan, David S Williams, Leonard H Augenlicht, Elizabeth Vincan, John M Mariadason
• Journal: American journal of physiology. Gastrointestinal and liver physiology (Am J Physiol Gastrointest Liver Physiol) Vol. 301 Issue 5 Pg. G856-64 (Nov 2011) ISSN: 1522-1547 [Electronic] United States
• PMID: 21836055 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Wnt Proteins
• beta Catenin
• Proto-Oncogene Proteins c-akt
• PTEN Phosphohydrolase

Topics

• Adenocarcinoma (genetics, metabolism, pathology)
• Adenoma (genetics, metabolism, pathology)
• Animals
• Epithelial Cells (metabolism, pathology)
• Intestinal Neoplasms (genetics, metabolism, pathology)
• Intestine, Small (metabolism, pathology)
• Mice
• Mice, Knockout
• PTEN Phosphohydrolase (genetics, metabolism)
• Phosphorylation
• Proto-Oncogene Proteins c-akt (genetics, metabolism)
• Signal Transduction (genetics)
• Wnt Proteins (genetics, metabolism)
• beta Catenin (genetics, metabolism)