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Overexpression of the Nonpancreatic Secretory Group II PLA₂ Messenger RNA and Protein in Colorectal Adenomas from Familial Adenomatous Polyposis Patients¹

Department of Biochemistry and Molecular Biology, Merck Frosst Center for Therapeutic Research, Pointe Claire-Dorval, Quebec [B. P. K., J. M., S. C.], and Departments of Pathology and Laboratory Medicine [C. S., L. X., T. H., B. B.] and Surgery [S. G.], Samuel Lunenfeld Research Institute [S. G., B. B.], Mount Sinai Hospital, University of Toronto, Toronto, Ontario, Canada

The synovial fluid or group II secretory phospholipase A₂ (sPLA₂) has been implicated in various inflammatory processes and has been shown to release arachidonic acid for prostaglandin biosynthesis. In human colorectal cancer, both arachidonic acid and eicosanoid levels are elevated. Recently, sPLA₂ has been identified as a candidate gene that modifies the Apc gene in the Min mouse, a murine model for familial adenomatous polyposis (FAP). Loss of sPLA₂ gene function results in susceptibility to the Min phenotype and the formation of multiple intestinal polyps, whereas mice expressing an active sPLA₂ gene are resistant to polyp formation. Therefore, there are two potentially contrasting roles for sPLA₂ in colon cancer; one is protection against polyp formation, and the other, the release of arachidonic acid for prostaglandin production and subsequent tumor promotion. To investigate these contrasting dual roles of sPLA₂, we have examined the expression and sequence of the sPLA₂ mRNA in normal mucosa and duodenal and colorectal polyps from FAP patients. In 11 of 14 patients, there was a significant increase in sPLA₂ mRNA levels in the adenoma over the normal tissue. In some cases, there was over 100-fold increase in mRNA levels in the adenoma compared with normal tissue. Analysis of multiple adenomatous polyps from individual patients revealed that not all polyps contained elevated levels of sPLA₂ mRNA. Immunoblot analysis also showed that sPLA₂ protein expression was elevated in adenoma over normal tissue in five of six FAP patients analyzed. Furthermore, sequence analysis of sPLA₂ mRNA present in these samples did not reveal mutations in the coding region. The implications of the up-regulation of sPLA₂ in FAP is not clear, but unlike the Min mouse model, it does not seem to have a significant effect on polyp formation. In contrast, the high level of sPLA₂ expression is more likely contributing to the elevated levels of arachidonic acid found in colorectal cancer and, in conjunction with the elevated expression of cyclooxygenase-2, could be another factor in tumor formation.

¹ This work was supported in part by funds from the National Cancer Institute of Canada (to B. B. and S. G.).

² To whom requests for reprints should be addressed, to B. P. K., at Department of Biochemistry and Molecular Biology, Merck Frosst Center Canada, Inc., P. O. Box 1005, Pointe Claire-Dorval, Quebec, H9R 4P8 Canada and to B. B. at Department of Pathology and Laboratory Medicine, Samuel Lunenfeld Research Institute, Mount Sinai Hospital, University of Toronto, Toronto, Ontario, M5G 1X5 Canada.

Received 5/28/97. Accepted 11/19/97.

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