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.
Highlights
Treatment of rodents with the DNA alkylating carcinogen, azoxymethane (AOM), induces colon tumors that exhibit a range of molecular alterations that is similar to that observed in human colorectal cancer [4,19, 22,32,33,36,56,64,67]
We found that expression of Pla2g2a provided strong resistance to AOM-induced colon tumorigenesis, in both genders and at 8 and 12 months of age
Similar to the phenotype observed in the ApcMin/+ mouse model [16,17], expression of Pla2g2a provided strong resistance to colon tumorigenesis in
Summary
Treatment of rodents with the DNA alkylating carcinogen, azoxymethane (AOM), induces colon tumors that exhibit a range of molecular alterations that is similar to that observed in human colorectal cancer [4,19, 22,32,33,36,56,64,67]. An example is the Mom (Modifier of Min-1) locus [21], a complex of genes on distal chromosome four that includes the Pla2g2a gene, which encodes for a secretory phospholipase that is naturally mutant in the C57BL/6 mouse strain [48]. Genetic evidence for Pla2g2a’s function as a suppressor of tumorigenesis was demonstrated by the reduction in tumors observed in C57BL/6 ApcMin/+ mice carrying a wildtype Pla2g2a transgene derived from the AKR strain [17]. The group IIA secretory phospholipase A2 gene, Pla2g2a, confers resistance to intestinal tumorigenesis in the ApcMin/+ mouse model. It is unclear how Pla2g2a exerts its tumor-suppressive effects and whether its mode of action depends on Apc-germline mutations
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