Document Detail


Pla2g2a attenuates colon tumorigenesis in azoxymethane-treated C57BL/6 mice; expression studies reveal Pla2g2a target genes and pathways.
MedLine Citation:
PMID:  19759415     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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. 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.
Authors:
Remond J A Fijneman; Lindsey K Bade; Johannes R Peham; Mark A van de Wiel; Victor W M van Hinsbergh; Gerrit A Meijer; Michael G O'Sullivan; Robert T Cormier
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Cellular oncology : the official journal of the International Society for Cellular Oncology     Volume:  31     ISSN:  1875-8606     ISO Abbreviation:  Cell. Oncol.     Publication Date:  2009  
Date Detail:
Created Date:  2009-09-17     Completed Date:  2009-12-21     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  101219418     Medline TA:  Cell Oncol     Country:  Netherlands    
Other Details:
Languages:  eng     Pagination:  345-56     Citation Subset:  IM    
Affiliation:
Department of Pathology, VU University Medical Center, Amsterdam, The Netherlands.
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MeSH Terms
Descriptor/Qualifier:
Animals
Azoxymethane / toxicity
Carcinogens / toxicity
Cell Transformation, Neoplastic / chemically induced,  genetics,  metabolism*,  pathology*
Colonic Neoplasms / chemically induced,  genetics,  metabolism*,  pathology*
Disease Models, Animal
Female
Gene Expression Regulation, Neoplastic* / drug effects
Group II Phospholipases A2 / genetics,  metabolism*
Male
Mice
Mice, Inbred C57BL
Mice, Transgenic
Chemical
Reg. No./Substance:
0/Carcinogens; 25843-45-2/Azoxymethane; EC 3.1.1.4/Group II Phospholipases A2; EC 3.1.1.4/Pla2g2a protein, mouse

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