Carcinogenesis, Vol. 21, No. 2, 133-138,
February 2000
© 2000 Oxford University Press
Cancer Biology |
Expression analysis of the group IIA secretory phospholipase A2 in mice with differential susceptibility to azoxymethane-induced colon tumorigenesis
Toxicology Program, Department of Pharmaceutical Sciences, University of Connecticut, 372 Fairfield Road, Storrs, CT 06269-2092, USA and
1 Cancer Research Institute, Tata Memorial Centre, Parel, Mumbai 400012, India
The murine non-pancreatic secretory phospholipase A2 (sPLA2) has been proposed as a tumor modifier of multiple intestinal neoplasia (Min). A genetic polymorphism in the mouse gene that causes a disruption in exon 3 results in loss of functional protein. Mouse strains with a disrupted sPLA2 gene are susceptible to the Min phenotype and develop numerous intestinal polyps, whereas mice with normal sPLA2 develop only a limited number of polyps. The following study was undertaken to test the hypothesis that sPLA2 plays an equivalent role in murine susceptibility to the colon carcinogen azoxymethane (AOM). sPLA2 status was confirmed by sequencing in mice that are highly susceptible (A/J), susceptible (SWR/J) and resistant (AKR/J) to AOM-induced tumorigenesis. Constitutive expression of sPLA2 mRNA was compared in small intestine and colon of untreated mice using semi-quantitative RT–PCR. Whereas mRNA expression was nearly absent in A/J mice, AKR/J mice exhibited extensive expression throughout the intestine. Despite the wild-type sPLA2 gene, colonic mRNA expression in SWR/J mice was significantly lower relative to AKR/J. Immunohistochemical analysis of sPLA2 protein confirmed the mRNA data. The effect of AOM on colonic sPLA2 expression was also examined. Twenty-four weeks after the last of six weekly injections of AOM (10 mg/kg i.p.), RT–PCR analysis of distal colons revealed a significant increase in mRNA in normal-appearing epithelium and tumor tissue from AOM-treated mice relative to controls. However, there was no corresponding increase in protein expression in A/J mice. The absence of sPLA2 expression within control colons of tumor-susceptible A/J mice together with low expression in SWR/J colons is consistent with its potential role as an intestinal tumor modifier, but the carcinogen-induced increase in expression raises doubts as to the significance of sPLA2 in inhibiting carcinogenesis.
Abbreviations: AOM, azoxymethane; COX, cyclooxygenase; DMH, 1,2-dimethylhydrazine; HPRT, hypoxanthine-guanine phosphoribosyltransferase; Min, multiple intestinal neoplasia; NSAIDs, non-steroidal anti-inflammatory drugs; PBS, phosphate-buffered saline; RT–PCR, reverse transcription–PCR; sPLA2, group IIA non-pancreatic secretory phospholipase A2.
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