Abstract
The aim of this study is to investigate the expression of three prostaglandin E synthase (PGES) isomers in colorectal cancer (CRC) tissue and to evaluate their relationship to clinicopathological factors and patient prognosis. Microsomal PGES (mPGES)-1, mPGES-2, cytosolic PGES (cPGES) and cyclooxygenase (COX)-2 protein expression were analyzed by real-time polymerase chain reaction and Western blot. The localization of each PGES and COX-2 protein was examined by immunohistochemistry in 155 surgical resections and correlated to clinicopathological factors and patient prognosis. mPGES-1 mRNA and protein levels were significantly higher in CRC than in paired normal tissues. mPGES-1 immunoreactivity localized in cancer cells in 43% of cases. mPGES-2 immunoreactivity was significantly more pronounced in cancer cells than in adjacent normal epithelium in 36% of cases. cPGES immunoreactivity was homogeneous in cancer cells and thus determined constitutive. mPGES-1 and mPGES-2 correlated with significantly worse prognosis in stage I–III patients. These results indicate that mPGES-1 and mPGES-2 may each play a role in CRC progression.
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Ulrich CM, Bigler J, Potter JD (2006) Non-steroidal anti-inflammatory drugs for cancer prevention: promise, perils and pharmacogenetics. Nat Rev Cancer 6:130–140
Sinicrope FA, Gill S (2004) Role of cyclooxygenase-2 in colorectal cancer. Cancer Metastasis Rev 23:63–75
Kawamori T, Rao CV, Seibert K et al (1998) Chemopreventive activity of celecoxib, a specific cyclooxygenase-2 inhibitor, against colon carcinogenesis. Cancer Res 58:409–412
Rahme E, Barkun AN, Toubouti Y et al (2003) The cyclooxygenase-2-selective inhibitors rofecoxib and celecoxib prevent colorectal neoplasia occurrence and recurrence. Gastroenterology 125:404–412
Bertagnolli MM, Eagle CJ, Zauber AG et al (2006) Celecoxib for the prevention of sporadic colorectal adenomas. N Engl J Med 355:873–884
Arber N, Eagle CJ, Spicak J et al (2006) Celecoxib for the prevention of colorectal adenomatous polyps. N Engl J Med 355:885–895
Chan AT, Ogino S, Fuchs CS (2007) Aspirin and the risk of colorectal cancer in relation to the expression of COX-2. N Engl J Med 356:2131–2142
Sinicrope FA (2006) Targeting cyclooxygenase-2 for prevention and therapy of colorectal cancer. Mol Carcinog 45:447–454
Wang D, Dubois RN (2006) Prostaglandins and cancer. Gut 55:115–122
Jakobsson PJ, Thoren S, Morgenstern R et al (1999) Identification of human prostaglandin E synthase: a microsomal, glutathione-dependent, inducible enzyme, constituting a potential novel drug target. Proc Natl Acad Sci U S A 96:7220–7225
Tanioka T, Nakatani Y, Semmyo N et al (2000) Molecular identification of cytosolic prostaglandin E2 synthase that is functionally coupled with cyclooxygenase-1 in immediate prostaglandin E2 biosynthesis. J Biol Chem 275:32775–32782
Tanikawa N, Ohmiya Y, Ohkubo H et al (2002) Identification and characterization of a novel type of membrane-associated prostaglandin E synthase. Biochem Biophys Res Commun 291:884–889
Han R, Tsui S, Smith TJ (2002) Up-regulation of prostaglandin E2 synthesis by interleukin-1beta in human orbital fibroblasts involves coordinate induction of prostaglandin-endoperoxide H synthase-2 and glutathione-dependent prostaglandin E2 synthase expression. J Biol Chem 277:16355–16364
Murakami M, Naraba H, Tanioka T et al (2000) Regulation of prostaglandin E2 biosynthesis by inducible membrane-associated prostaglandin E2 synthase that acts in concert with cyclooxygenase-2. J Biol Chem 275:32783–32792
Murakami M, Nakashima K, Kamei D et al (2003) Cellular prostaglandin E2 production by membrane-bound prostaglandin E synthase-2 via both cyclooxygenases-1 and -2. J Biol Chem 278:37937–37947
Yoshimatsu K, Golijanin D, Paty PB et al (2001) Inducible microsomal prostaglandin E synthase is overexpressed in colorectal adenomas and cancer. Clin Cancer Res 7:3971–3976
van Rees BP, Sabula A, Thorne S et al (2003) Expression of microsomal prostaglandin E synthase-1 in intestinal type gastric adenocarcinoma and in gastric cancer cell lines. Int J Cancer 107:551–556
Mehrotra S, Morimiya A, Agarwal B et al (2006) Microsomal prostaglandin E2 synthase-1 in breast cancer: a potential target for therapy. J Pathol 208:356–363
Rask K, Zhu Y, Wang W et al (2006) Ovarian epithelial cancer: a role for PGE2-synthesis and signalling in malignant transformation and progression. Mol Cancer 5:62
Gudis K, Tatsuguchi A, Wada K et al (2007) Clinical significance of prostaglandin E synthase expression in gastric cancer tissue. Hum Pathol 38:1826–1835
Nakanishi M, Montrose DC, Clark P et al (2008) Genetic deletion of mPGES-1 suppresses intestinal tumorigenesis. Cancer Res 68:3251–3259
Kamei D, Murakami M, Nakatani Y et al (2003) Potential role of microsomal prostaglandin E synthase-1 in tumorigenesis. J Biol Chem 278:19396–19405
Gudis K, Tatsuguchi A, Wada K et al (2005) Microsomal prostaglandin E synthase (mPGES)-1, mPGES-2 and cytosolic PGES expression in human gastritis and gastric ulcer tissue. Lab Invest 85:225–236
Guo H, Tatsuguchi A, Shinji S et al (2006) Cyclooxygenase-2 expression correlates with membrane-type-1 matrix metalloproteinase expression in colorectal cancer tissue. Dis Colon Rectum 49:1184–1192
Tatsuguchi A, Kishida T, Fujimori S et al (2006) Differential expression of cyclo-oxygenase-2 and nuclear beta-catenin in colorectal cancer tissue. Aliment Pharmacol Ther 24(Suppl 4):153–159
Stichtenoth DO, Thoren S, Bian H et al (2001) Microsomal prostaglandin E synthase is regulated by proinflammatory cytokines and glucocorticoids in primary rheumatoid synovial cells. J Immunol 167:469–474
Fux R, Schwab M, Thon KP et al (2005) Cyclooxygenase-2 expression in human colorectal cancer is unrelated to overall patient survival. Clin Cancer Res 11:4754–4760
Tsujii M, Kawano S, Tsuji S et al (1998) Cyclooxygenase regulates angiogenesis induced by colon cancer cells. Cell 93:705–716
Tatsuguchi A, Matsui K, Shinji Y et al (2004) Cyclooxygenase-2 expression correlates with angiogenesis and apoptosis in gastric cancer tissue. Hum Pathol 35:488–495
Tanaka S, Tatsuguchi A, Futagami S et al (2006) Monocyte chemoattractant protein 1 and macrophage cyclooxygenase 2 expression in colonic adenoma. Gut 55:54–61
Kudo I, Murakami M (2005) Prostaglandin e synthase, a terminal enzyme for prostaglandin E2 biosynthesis. J Biochem Mol Biol 38:633–638
Watanabe K, Ohkubo H, Niwa H et al (2003) Essential 110Cys in active site of membrane-associated prostaglandin E synthase-2. Biochem Biophys Res Commun 306:577–581
Hu J, Meng Q, Roy SK et al (2002) A Novel Transactivating Factor That Regulates Interferon-gamma-dependent Gene Expression. J Biol Chem 277:30253–30263
Wright KL, Weaver SA, Patel K et al (2004) Differential regulation of prostaglandin E biosynthesis by interferon-gamma in colonic epithelial cells. Br J Pharmacol 141:1091–1097
Bresalier RS, Sandler RS, Quan H et al (2005) Cardiovascular events associated with rofecoxib in a colorectal adenoma chemoprevention trial. N Engl J Med 352:1092–1102
Cheng Y, Wang M, Yu Y et al (2006) Cyclooxygenases, microsomal prostaglandin E synthase-1, and cardiovascular function. J Clin Invest 116:1391–1399
Elander N, Ungerbäck J, Olsson H et al (2008) Genetic deletion of mPGES-1 accelerates intestinal tumorigenesis in APC(Min/+) mice. Biochem Biophys Res Commun 372:249–253
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Seo, T., Tatsuguchi, A., Shinji, S. et al. Microsomal prostaglandin E synthase protein levels correlate with prognosis in colorectal cancer patients. Virchows Arch 454, 667–676 (2009). https://doi.org/10.1007/s00428-009-0777-z
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DOI: https://doi.org/10.1007/s00428-009-0777-z