Pla2g2a attenuates colon tumorigenesis in azoxymethane-treated C57BL/6 mice; expression studies reveal Pla2g2a target genes and pathways.
BACKGROUND
The group IIA secretory phospholipase A2 gene, Pla2g2a, confers resistance to intestinal tumorigenesis in the Apc(Min/+) 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 beta-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.


CONCLUSIONS
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.
Fijneman
Remond J A
RJ
Department of Pathology, VU University Medical Center, Amsterdam, The Netherlands.
Bade
Lindsey K
LK
Peham
Johannes R
JR
van de Wiel
Mark A
MA
van Hinsbergh
Victor W M
VW
Meijer
Gerrit A
GA
O'Sullivan
Michael G
MG
Cormier
Robert T
RT
D000818:Animals; D001397:Azoxymethane / Q000633:toxicity; D002273:Carcinogens / Q000633:toxicity; D002471:Cell Transformation, Neoplastic / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D003110:Colonic Neoplasms / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D004195:Disease Models, Animal; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D054501:Group II Phospholipases A2 / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic
D002273:Carcinogens; D054501:Group II Phospholipases A2; C516288:Pla2g2a protein, mouse; D001397:Azoxymethane