Expression analysis of the group IIA secretory phospholipase A(2) in mice with differential susceptibility to azoxymethane-induced colon tumorigenesis

The murine non-pancreatic secretory phospholipase A(2) (sPLA(2)) has been p roposed as a tumor modifier of multiple intestinal neoplasia (Min). A genet ic polymorphism in the mouse gene that causes a disruption in exon 3 result s in loss of functional protein. Mouse strains with a disrupted sPLA(2) gen e are susceptible to the Min phenotype and develop numerous intestinal poly ps, whereas mice with normal sPLA(2) develop only a limited number of polyp s, The following study was undertaken to test the hypothesis that sPLA(2) p lays an equivalent role in murine susceptibility to the colon carcinogen az oxymethane (AOM), sPLA(2) status was confirmed by sequencing in mice that a re highly susceptible (A/J), susceptible (SWR/J) and resistant (AKR/J) to A OM-induced tumorigenesis. Constitutive expression of sPLA(2) mRNA was compa red 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 e xhibited extensive expression throughout the intestine. Despite the wild-ty pe sPLA(2) gene, colonic mRNA expression in SWR/J mice was significantly lo wer relative to AKR/J, Immunohistochemical analysis of sPLA(2) protein conf irmed the mRNA data. The effect of AOM on colonic sPLA(2) expression was al so examined. Twenty-four weeks after the last of six weekly injections of A OM (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 incr ease in protein expression in A/J mice. The absence of sPLA(2) expression w ithin control colons of tumor-susceptible A/J mice together with low expres sion in SWR/J colons is consistent with its potential role as an intestinal tumor modifier, but the carcinogen-induced increase in expression raises d oubts as to the significance of sPLA(2) in inhibiting carcinogenesis.