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Molecular Oncology, Markers, Clinical Correlates |
Departments of Medicine [K. Y., K. S., A. J. D.] and Pathology [R. A. D.], Weill Medical College of Cornell University and Strang Cancer Prevention Center, New York, New York 10021; Departments of Urology [D. G.], Surgery [P. B. P.], and Pathology [R. A. S.], Memorial Sloan-Kettering Cancer Center, New York, New York 10021; and Department of Medical Biochemistry and Biophysics, Karolinska Institute, S-171 77 Stockholm, Sweden [P-J. J.]
Recently, an inducible microsomal human prostaglandin E synthase (mPGES) was identified. This enzyme converts the cyclooxygenase (COX) product prostaglandin (PG) H2 to PGE2, an eicosanoid that has been linked to carcinogenesis. Increased amounts of PGE2 have been observed in many tumor types including colorectal adenomas and cancers. To further elucidate the mechanism responsible for increased levels of PGE2 in colorectal tumors, we determined the amounts of mPGES and COX-2 in 18 paired samples (tumor and adjacent normal) of colorectal cancer. With immunoblot analysis, mPGES was overexpressed in 83% of colorectal cancers. COX-2 was also commonly up-regulated in these tumors; marked differences in the extent of up-regulation of mPGES and COX-2 were observed in individual tumors. Immunohistochemistry revealed increased mPGES immunoreactivity in neoplastic cells in both colorectal adenomas and cancers compared with adjacent normal colonic epithelium. Cell culture was used to investigate the regulation of mPGES and COX-2. Chenodeoxycholate markedly induced COX-2 but not mPGES in colorectal cancer cells. Tumor necrosis factor-
induced both mPGES and COX-2, but the time course and magnitude of induction differed. As reported previously for COX-2, overexpressing Ras caused a several-fold increase in mPGES promoter activity. Taken together, our results suggest that overexpression of mPGES in addition to COX-2 contributes to increased amounts of PGE2 in colorectal adenomas and cancer. The mechanisms controlling the expression of these two enzymes are not identical.
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