Secretory phospholipase Pla2g2a confers resistance to intestinal tumorigenesis

Abstract

Individuals inheriting the same mutation predisposing to cancer may show very different outcomes, ranging from early aggressive cancer to disease-free survival. Experimental mouse models can provide a powerful tool to identify factors in the environment and genetic background that account for such modifications. The Min mouse strain, in which the ApcMin mutation disrupts the mouse homologue of the human familial polyposis gene, develops intestinal neoplasms whose multiplicity is strongly affected by genetic background. We previously mapped a strong modifier locus, Mom1 (modifier of Min-1), to a 4-cM region on mouse chromosome 4 containing a candidate gene Pla2g2a encoding a secretory phospholipase. Here, we report that a cosmid transgene overexpressing Pla2g2a caused a reduction in tumour multiplicity and size, comparable to that conferred by a single copy of the resistance allele of Mom1. These results offer strong evidence that this secretory phospholipase can provide active tumour resistance. The association of Pla2g2a with Mom1 thus withstands a strong functional test and is likely to represent the successful identification of a polymorphic quantitative trait locus in mammals.

RUNX3 is multifunctional in carcinogenesis of multiple solid tumors

“…Moreover, it is noteworthy that genes mapping to human 1p36 show syntenic conservation with mouse chromosome 4, lending weight to the theory that this region harbors a cluster of tumor suppressor genes, which work cooperatively and when deleted would drive tumorigenesis (Bagchi and Mills, 2008). The 1p36 tumor suppressor genes include retinoblastoma protein-interacting zincfinger (RIZ)1, chromodomain helicase DNA-binding protein 5 (CHD5), secretory phospholipase PLA2G2A (Modifier of Min-1) (Cormier et al, 1997), and TP73. Interestingly, RIZ1, also known as PRDM2, is a member of the nuclear histone/protein methyltransferase superfamily that methylates histone 3 Lys 9 (H3K9) residues, whereas CHD5 belongs to the SWI/SNF chromatin modifier family.…”

Variation in Gene Expression Patterns in Human Gastric Cancers

“…Patients whose gastric cancers expressed PLA2G2A, the gene encoding the group IIa secreted phospholipase A2, at high levels, had a highly significant survival advantage (p Ͻ 0.002). The murine ortholog of PLA2G2A, has been shown genetically to limit the severity of intestinal neoplasia in the Apc min1/ϩ mouse, a mouse model of familial adenomatous polyposis, suggesting that PLA2G2A may play a similar role in suppressing progression of human gastric cancer (MacPhee et al, 1995;Cormier et al, 1997). A more extensive analysis and discussion of the association between PLA2G2A and gastric cancer progression is reported separately (Leung et al, 2002).…”

Novel loci controlling lymphocyte proliferative response to cytokines and their clustering with loci controlling autoimmune reactions, macrophage function and lung tumor susceptibility

“…3 Tlsr3 (thymic lymphoma suppressor region 3) and Stmn1 (stathmin 1) that influence both lymphocyte growth and cancer development as well as another lung tumor susceptibility locus, Sluc21, are localized in the vicinity of Cinda3, but more centromerically (http://www.informatics.jax.org). As discussed above, much closer to Cinda3 are several other loci affecting cancer development: Sluc6 (susceptibility to lung cancer 6), 22 ssic1 (susceptibility to small intestinal cancer1) 25 and Mom1 (modifier of Min-1), which is involved in intestinal neoplasms and was identified as Pla2g2a (phospholipase A2, group IIA), 26,27 an enzyme with pleiotropic functions that has been implicated in many different biologic responses, including inflammation, cell signaling and antimicrobial activity. 28,29 With the exception of a short centromeric segment, the chromosome 19 in the strain OcB-9 is of B10.O20 origin.…”