Reduced expression of cyclooxygenase 2 proteins in hereditary nonpolyposis colorectal cancers relative to sporadic cancers.
OBJECTIVE
Cyclooxygenase (COX) enzymes catalyze the conversion of arachidonic acid to prostaglandins. Evidence suggests that nonsteroidal anti-inflammatory drugs reduce the risk of colorectal cancer (CRC) and that this effect is mediated through COX inhibition. We analyzed and compared expression of the inducible COX-2 isoform in colorectal neoplasms from patients with hereditary nonpolyposis colorectal cancer (HNPCC), familial adenomatous polyposis (FAP), and sporadic CRC. Given that COX-2 is induced by transforming growth factor (TGF)-beta and that TGF-beta type II receptor (RII) mutations are found in HNPCCs, we determined the relationship between RII status and COX-2 expression.


METHODS
COX-2 protein expression was determined in colorectal epithelia using immunohistochemistry and Western blotting. Patients with HNPCC had known mutations in hMLH1 or hMSH2 genes and/or met the Amsterdam criteria. In CRCs from HNPCC cases, mutations were sought in the coding region of the RII gene using the polymerase chain reaction.


RESULTS
COX-2 was detected in adenomas from 2 of 3 HNPCC, 6 of 7 FAP, and 5 of 8 sporadic cases. In CRCs, COX-2 staining was found in 16 of 24 (67%) HNPCC vs. 24 of 26 (92%) sporadic cases (P = 0.035) and in 2 of 2 FAP cases. Staining intensity was reduced in HNPCCs compared with sporadic CRCs (P = 0.035). Staining localized to the cytoplasm of neoplastic cells; normal epithelial cells were negative for COX-2. Overexpression of COX-2 in CRCs relative to normal mucosa was confirmed by Western blotting. TGF-beta RII mutations were detected in 12 of 14 HNPCCs examined, including 3 of 4 COX-2-negative and 9 of 10 COX-2-positive cancers.


CONCLUSIONS
The frequency and intensity of COX-2 expression was significantly reduced in HNPCCs relative to sporadic CRCs, and was not a consequence of RII mutations. Given that many HNPCCs express COX-2, inhibition of this enzyme may be an important strategy to prevent CRC in these patients.
Department of Gastrointestinal Medical Oncology and Digestive Diseases, University of Texas M. D. Anderson Cancer Center, Houston, Texas, USA. fsinicro@notes.mdacc.tmc.edu
F A
FA
Sinicrope
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Lemoine
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Xi
P M
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Lynch
K R
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Cleary
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Shen
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Frazier
D011125:Adenomatous Polyposis Coli / Q000201:enzymology; D015153:Blotting, Western; D003123:Colorectal Neoplasms, Hereditary Nonpolyposis / Q000201:enzymology*; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D006801:Humans; D007150:Immunohistochemistry; D007527:Isoenzymes / Q000032:analysis* / Q000187:drug effects / Q000276:immunology; D008565:Membrane Proteins; D009154:Mutation; D011451:Prostaglandin-Endoperoxide Synthases / Q000032:analysis* / Q000187:drug effects / Q000276:immunology; D018125:Receptors, Transforming Growth Factor beta / Q000235:genetics; D014407:Tumor Cells, Cultured
D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D007527:Isoenzymes; D008565:Membrane Proteins; D018125:Receptors, Transforming Growth Factor beta; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases