Article type: Research Article
Authors: Fijneman, Remond J.A.; ; | Bade, Lindsey K.; | Peham, Johannes R. | van de Wiel, Mark A.; | van Hinsbergh, Victor W.M.; | Meijer, Gerrit A. | O'Sullivan, Michael G. | Cormier, Robert T.;
Affiliations: Department of Pathology, VU University Medical Center, Amsterdam, The Netherlands | Department of Biochemistry & Molecular Biology, University of Minnesota Medical School, Duluth, MN, USA | Department of Epidemiology and Biostatistics, VU University Medical Center, Amsterdam, The Netherlands | Department of Mathematics, VU University, Amsterdam, The Netherlands | Department of Medical Oncology, VU University Medical Center, Amsterdam, The Netherlands | Department of Physiology, VU University Medical Center, Amsterdam, The Netherlands | University of Minnesota College of Veterinary Medicine, St. Paul, MN, USA | Genetics and Cell Biology, University of Minnesota Medical School, Minneapolis, MN, USA
Note: [] These authors contributed equally to the study.
Note: [] Corresponding author: Robert T. Cormier, Department of Biochemistry & Molecular Biology, University of Minnesota Medical School, 1035 University Drive, Duluth, MN 55812, USA. Tel.: +1 218 726 8625; Fax: +1 218 726 8014; E-mail: rcormier@d.umn.edu.
Abstract: Background: The group IIA secretory phospholipase A2 gene, Pla2g2a, confers resistance to intestinal tumorigenesis in the ApcMin/+ mouse model. However, it is unclear how Pla2g2a exerts its tumor-suppressive effects and whether its mode of action depends on Apc-germline mutations. Methods: We tested whether expression of a Pla2g2a transgene provides protection against carcinogen-induced colon tumors, and examined whether the normal colon microenvironment is modulated by Pla2g2a expression. Results: Pla2g2a strongly inhibited colon tumorigenesis in mice following treatment with the DNA alkylating agent azoxymethane (AOM). Moreover, AOM-induced duodenal tumors were also attenuated by Pla2g2a expression. These tumors demonstrated upregulation of β-catenin, indicative of involvement of the Wnt signaling pathway. Comparison of genome-wide microarray expression profiles of healthy (non-pathologic) colon tissues from Pla2g2a-transgenic to non-transgenic mice revealed 382 genes that were differentially expressed, comprising clusters of genes involved in inflammation and microbial defense, cell signaling and cell cycle, transactivation, apoptosis and mitochondrial function, DNA repair, and lipid and energy metabolism. Pathway analysis using Gene Set Enrichment Analysis (GSEA) indicated that Pla2g2a suppresses the expression of interferon-induced genes. Conclusion: Our results demonstrate that Pla2g2a attenuates colon tumorigenesis independent of Apc-germline mutations, and reveal Pla2g2a target genes and pathways in non-pathologic colon microenvironment that influence conditions for colorectal cancer development.
Keywords: Colorectal cancer, Pla2g2a, microarray expression analysis, transgenic mice
DOI: 10.3233/CLO-2009-0480
Journal: Analytical Cellular Pathology, vol. 31, no. 5, pp. 345-356, 2009
