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Clinical Implications of Microsomal Prostaglandin E Synthase-1 Overexpression in Human Non–Small-Cell Lung Cancer

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Abstract

Background

Microsomal prostaglandin E synthase-1 (mPGES-1) has recently been found to overexpress in human cancers, including non–small-cell lung cancer (NSCLC). However, the clinical value is largely unknown. The aim of this study was to investigate the associations between mPGES-1 expression in NSCLC and the clinical characteristics and survival outcome.

Methods

Between 2001 and 2003, paired fresh tumorous and nontumorous samples were prospectively procured from patients undergoing surgery for NSCLC. The expression of mPGES-1 was assessed by using Western blot in 93 subjects and reverse transcriptase-polymerase chain reaction in 35. Overexpression of mPGES-1 was defined as a more than 2-fold expression in the tumorous sample compared with the corresponding nontumorous one. Immunohistochemistry was used to confirm its localization to the tumor cells. In a subset of 30 cases, cyclooxygenase-2 (COX-2) was also analyzed to assess its association with mPGES-1.

Results

The protein and messenger RNA of mPGES-1 were both expressed at higher levels in the tumor samples (P < .001 and P = .006, respectively). The expressions of mPGES-1 and COX-2 were unrelated (P = .715). Overexpression of mPGES-1 protein was observed in 61 (65.6%) of 93 patients, but it was not significantly associated with the clinicopathologic characteristics or overall and disease-free survivals. However, mPGES-1 overexpression seemed to be associated with the likelihood of subsequent pulmonary metastases and a lower tendency for developing bony metastases (P = .001 and P = .006, respectively).

Conclusions

Our results demonstrated that mPGES-1 was overexpressed in NSCLC, unassociated with COX-2. Overexpression of mPGES-1 per se was not a prognostic indicator, but it might be implicated in the organ preference of metastasis.

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References

  1. Health Annual Statistics Report: 2003. Bureau of Health Promotion, Department of Health, The Executive Yuan. Taiwan, 2003

  2. Spira A, Ettinger DS. Multidisciplinary management of lung cancer. N Engl J Med 2004;350:379–92

    Article  PubMed  CAS  Google Scholar 

  3. Thun MJ, Namboodiri MM, Calle EE, Flanders WD, Heath CW Jr. Aspirin use and risk of fatal cancer. Cancer Res 1993;53:1322–7

    PubMed  CAS  Google Scholar 

  4. Watson DM, Kelly RW, Miller WR. Prostaglandins and prognosis in human breast cancer. Br J Cancer 1987;56:367–70

    PubMed  CAS  Google Scholar 

  5. McLemore TL, Hubbard WC, Litterst CL, et al. Profiles of prostaglandin biosynthesis in normal lung and tumor tissue from lung cancer patients. Cancer Res 1988;48:3140–7

    PubMed  CAS  Google Scholar 

  6. Snyderman CH, Milanovich M, Wagner RL, Johnson JT. Prognostic significance of prostaglandin E2 production in fresh tissues of head and neck cancer patients. Head Neck 1995;17:108–13

    Article  PubMed  CAS  Google Scholar 

  7. Zweifel BS, Davis TW, Ornberg RL, Masferrer JL. Direct evidence for a role of cyclooxygenase 2-derived prostaglandin E2 in human head and neck xenograft tumors. Cancer Res 2002;62:6706–11

    PubMed  CAS  Google Scholar 

  8. Kawamori T, Uchiya N, Sugimura T, Wakabayashi K. Enhancement of colon carcinogenesis by prostaglandin E2 administration. Carcinogenesis 2003;24:985–90

    Article  PubMed  CAS  Google Scholar 

  9. Sheng H, Shao J, Washington MK, DuBois RN. Prostaglandin E2 increases growth and motility of colorectal carcinoma cells. J Biol Chem 2001;276:18075–81

    Article  PubMed  CAS  Google Scholar 

  10. Pai R, Soreghan B, Szabo IL, Pavelka M, Baatar D, Tarnawski AS. Prostaglandin E2 transactivates EGF receptor: a novel mechanism for promoting colon cancer growth and gastrointestinal hypertrophy. Nat Med 2002;8:289–93

    Article  PubMed  CAS  Google Scholar 

  11. Jakobsson PJ, Thoren S, Morgenstern R, Samuelsson B. 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 1999;96:7220–5

    Article  PubMed  CAS  Google Scholar 

  12. Tanioka T, Nakatani Y, Semmyo N, Murakami M, Kudo I. Molecular identification of cytosolic prostaglandin E2 synthase that is functionally coupled with cyclooxygenase-1 in immediate prostaglandin E2 biosynthesis. J Biol Chem 2000;275:32775–82

    Article  PubMed  CAS  Google Scholar 

  13. Tanikawa N, Ohmiya Y, Ohkubo H, et al. Identification and characterization of a novel type of membrane-associated prostaglandin E synthase. Biochem Biophys Res Commun 2002;291:884–9

    Article  PubMed  CAS  Google Scholar 

  14. Murakami M, Naraba H, Tanioka T, et al. Regulation of prostaglandin E2 biosynthesis by inducible membrane-associated prostaglandin E2 synthase that acts in concert with cyclooxygenase-2. J Biol Chem 2000;275:32783–92

    Article  PubMed  CAS  Google Scholar 

  15. Murakami M, Nakashima K, Kamei D, et al. Cellular prostaglandin E2 production by membrane-bound prostaglandin E synthase-2 via both cyclooxygenases-1 and -2. J Biol Chem 2003;278:37937–47

    Article  PubMed  CAS  Google Scholar 

  16. Murakami M, Nakatani Y, Tanioka T, Kudo I. Prostaglandin E synthase. Prostaglandins Other Lipid Mediat 2002;68–9:383–99

    Article  Google Scholar 

  17. Yamagata K, Matsumura K, Inoue W, et al. Coexpression of microsomal-type prostaglandin E synthase with cyclooxygenase-2 in brain endothelial cells of rats during endotoxin-induced fever. J Neurosci 2001;21:2669–77

    PubMed  CAS  Google Scholar 

  18. Soslow RA, Dannenberg AJ, Rush D, et al. COX-2 is expressed in human pulmonary, colonic, and mammary tumors. Cancer 2000;89:2637–45

    Article  PubMed  CAS  Google Scholar 

  19. Hida T, Yatabe Y, Achiwa H, et al. Increased expression of cyclooxygenase 2 occurs frequently in human lung cancers, specifically in adenocarcinomas. Cancer Res 1998;58:3761–4

    PubMed  CAS  Google Scholar 

  20. Wolff H, Saukkonen K, Anttila S, Karjalainen A, Vainio H, Ristimaki A. Expression of cyclooxygenase-2 in human lung carcinoma. Cancer Res 1998;58:4997–5001

    PubMed  CAS  Google Scholar 

  21. Achiwa H, Yatabe Y, Hida T, et al. Prognostic significance of elevated cyclooxygenase 2 expression in primary, resected lung adenocarcinomas. Clin Cancer Res 1999;5:1001–5

    PubMed  CAS  Google Scholar 

  22. Khuri FR, Wu H, Lee JJ, et al. Cyclooxygenase-2 overexpression is a marker of poor prognosis in stage I non-small cell lung cancer. Clin Cancer Res 2001;7:861–7

    PubMed  CAS  Google Scholar 

  23. Altorki NK, Keresztes RS, Port JL, et al. Celecoxib, a selective cyclo-oxygenase-2 inhibitor, enhances the response to preoperative paclitaxel and carboplatin in early-stage non-small-cell lung cancer. J Clin Oncol 2003;21:2645–50

    Article  PubMed  CAS  Google Scholar 

  24. Bombardier C, Laine L, Reicin A, et al. Comparison of upper gastrointestinal toxicity of rofecoxib and naproxen in patients with rheumatoid arthritis. VIGOR Study Group. N Engl J Med 2000;343:1520–8

    Article  PubMed  CAS  Google Scholar 

  25. Fitzgerald GA. Coxibs and cardiovascular disease. N Engl J Med 2004;351:1709–11

    Article  PubMed  CAS  Google Scholar 

  26. Yoshimatsu K, Altorki NK, Golijanin D, et al. Inducible prostaglandin E synthase is overexpressed in non-small cell lung cancer. Clin Cancer Res 2001;7:2669–74

    PubMed  CAS  Google Scholar 

  27. Ermert L, Dierkes C, Ermert M. Immunohistochemical expression of cyclooxygenase isoenzymes and downstream enzymes in human lung tumors. Clin Cancer Res 2003;9:1604–10

    PubMed  CAS  Google Scholar 

  28. Travis WD, Colby TV, Corrin B, Shimosato Y, Brambilla E. Histological Typing of Lung and Pleural Tumours. 3rd ed. Berlin: Springer, 1999

    Google Scholar 

  29. Mountain CF. Revisions in the International System for Staging Lung Cancer. Chest 1997;111:1710–7

    Article  PubMed  CAS  Google Scholar 

  30. Zhang F, Altorki NK, Wu YC, Soslow RA, Subbaramaiah K, Dannenberg AJ. Duodenal reflux induces cyclooxygenase-2 in the esophageal mucosa of rats: evidence for involvement of bile acids. Gastroenterology 2001;121:1391–9

    Article  PubMed  CAS  Google Scholar 

  31. Hsueh CT, Kelsen D, Schwartz GK. UCN-01 suppresses thymidylate synthase gene expression and enhances 5-fluorouracil-induced apoptosis in a sequence-dependent manner. Clin Cancer Res 1998;4:2201–6

    PubMed  CAS  Google Scholar 

  32. Soler M, Camacho M, Escudero JR, Iniguez MA, Vila L. Human vascular smooth muscle cells but not endothelial cells express prostaglandin E synthase. Circ Res 2000;87:504–7

    PubMed  CAS  Google Scholar 

  33. Fujita T, Matsui M, Takaku K, et al. Size- and invasion-dependent increase in cyclooxygenase 2 levels in human colorectal carcinomas. Cancer Res 1998;58:4823–6

    PubMed  CAS  Google Scholar 

  34. Hsueh CT, Dolnick BJ. Folate-binding protein mRNA is decreased in methotrexate-resistant KB cells. Oncol Res 1992;4:497–505

    PubMed  CAS  Google Scholar 

  35. Yoshimatsu K, Golijanin D, Paty PB, et al. Inducible microsomal prostaglandin E synthase is overexpressed in colorectal adenomas and cancer. Clin Cancer Res 2001;7:3971–6

    PubMed  CAS  Google Scholar 

  36. van Rees BP, Sivula A, Thoren S, et al. Expression of microsomal prostaglandin E synthase-1 in intestinal type gastric adenocarcinoma and in gastric cancer cell lines. Int J Cancer 2003;107:551–6

    Article  PubMed  Google Scholar 

  37. Cohen EG, Almahmeed T, Du B, et al. Microsomal prostaglandin E synthase-1 is overexpressed in head and neck squamous cell carcinoma. Clin Cancer Res 2003;9:3425–30

    PubMed  CAS  Google Scholar 

  38. Jabbour HN, Milne SA, Williams AR, Anderson RA, Boddy SC. Expression of COX-2 and PGE synthase and synthesis of PGE2 in endometrial adenocarcinoma: a possible autocrine/paracrine regulation of neoplastic cell function via EP2/EP4 receptors. Br J Cancer 2001;85:1023–31

    Article  PubMed  CAS  Google Scholar 

  39. Golijanin D, Tan JY, Kazior A, et al. Cyclooxygenase-2 and microsomal prostaglandin E synthase-1 are overexpressed in squamous cell carcinoma of the penis. Clin Cancer Res 2004;10:1024–31

    Article  PubMed  CAS  Google Scholar 

  40. Endoh H, Tomida S, Yatabe Y, et al. Prognostic model of pulmonary adenocarcinoma by expression profiling of eight genes as determined by quantitative real-time reverse transcriptase polymerase chain reaction. J Clin Oncol 2004;22:811–9

    Article  PubMed  CAS  Google Scholar 

  41. Kamei D, Murakami M, Nakatani Y, Ishikawa Y, Ishii T, Kudo I. Potential role of microsomal prostaglandin E synthase-1 in tumorigenesis. J Biol Chem 2003;278:19396–405

    Article  PubMed  CAS  Google Scholar 

  42. Vane JR. Prostacyclin: a hormone with a therapeutic potential. The Sir Henry Dale Lecture for 1981. J Endocrinol 1982;95:3P–43P

    PubMed  CAS  Google Scholar 

  43. Honn KV, Cicone B, Skoff A. Prostacyclin: a potent antimetastatic agent. Science 1981;212:1270–2

    Article  PubMed  CAS  Google Scholar 

  44. Keith RL, Miller YE, Hoshikawa Y, et al. Manipulation of pulmonary prostacyclin synthase expression prevents murine lung cancer. Cancer Res 2002;62:734–40

    PubMed  CAS  Google Scholar 

  45. Blaine SA, Meyer AM, Hurteau G, et al. Targeted over-expression of mPGES-1 and elevated PGE2 production is not sufficient for lung tumorigenesis in mice. Carcinogenesis 2005;26:209–17

    Article  PubMed  CAS  Google Scholar 

  46. Puxeddu E, Mitsutake N, Knauf JA, et al. Microsomal prostaglandin E2 synthase-1 is induced by conditional expression of RET/PTC in thyroid PCCL3 cells through the activation of the MEK-ERK pathway. J Biol Chem 2003;278:52131–8

    Article  PubMed  CAS  Google Scholar 

  47. Naraba H, Yokoyama C, Tago N, et al. Transcriptional regulation of the membrane-associated prostaglandin E2 synthase gene. Essential role of the transcription factor Egr-1. J Biol Chem 2002;277:28601–8

    Article  PubMed  CAS  Google Scholar 

  48. Subbaramaiah K, Yoshimatsu K, Scherl E, et al. Microsomal prostaglandin E synthase-1 is overexpressed in inflammatory bowel disease. Evidence for involvement of the transcription factor Egr-1. J Biol Chem 2004;279:12647–58

    Article  PubMed  CAS  Google Scholar 

  49. Catley MC, Chivers JE, Cambridge LM, et al. IL-1beta-dependent activation of NF-kappaB mediates PGE2 release via the expression of cyclooxygenase-2 and microsomal prostaglandin E synthase. FEBS Lett 2003;547:75–9

    Article  PubMed  CAS  Google Scholar 

  50. Masuko-Hongo K, Berenbaum F, Humbert L, Salvat C, Goldring MB, Thirion S. Up-regulation of microsomal prostaglandin E synthase 1 in osteoarthritic human cartilage: critical roles of the ERK-1/2 and p38 signaling pathways. Arthritis Rheum 2004;50:2829–38

    Article  PubMed  CAS  Google Scholar 

  51. Giannico G, Mendez M, LaPointe MC. Regulation of the membrane-localized prostaglandin E synthases mPGES-1 and mPGES-2 in cardiac myocytes and fibroblasts. Am J Physiol Heart Circ Physiol 2005;288:H165–74

    Article  PubMed  CAS  Google Scholar 

  52. Gasparini G, Longo R, Sarmiento R, Morabito A. Inhibitors of cyclo-oxygenase 2: a new class of anticancer agents? Lancet Oncol 2003;4:605–15

    Article  PubMed  CAS  Google Scholar 

  53. Gilhooly EM, Rose DP. The association between a mutated ras gene and cyclooxygenase-2 expression in human breast cancer cell lines. Int J Oncol 1999;15:267–70

    PubMed  CAS  Google Scholar 

  54. Subbaramaiah K, Telang N, Ramonetti JT, et al. Transcription of cyclooxygenase-2 is enhanced in transformed mammary epithelial cells. Cancer Res 1996;56:4424–9

    PubMed  CAS  Google Scholar 

  55. Kojima F, Naraba H, Sasaki Y, Okamoto R, Koshino T, Kawai S. Coexpression of microsomal prostaglandin E synthase with cyclooxygenase-2 in human rheumatoid synovial cells. J Rheumatol 2002;29:1836–42

    PubMed  CAS  Google Scholar 

  56. Cipollone F, Prontera C, Pini B, et al. Overexpression of functionally coupled cyclooxygenase-2 and prostaglandin E synthase in symptomatic atherosclerotic plaques as a basis of prostaglandin E(2)-dependent plaque instability. Circulation 2001;104:921–7

    Article  PubMed  CAS  Google Scholar 

  57. Thoren S, Jakobsson PJ. Coordinate up- and down-regulation of glutathione-dependent prostaglandin E synthase and cyclooxygenase-2 in A549 cells. Inhibition by NS-398 and leukotriene C4. Eur J Biochem 2000;267:6428–34

    Article  PubMed  CAS  Google Scholar 

  58. Amano H, Hayashi I, Endo H, et al. Host prostaglandin E(2)-EP3 signaling regulates tumor-associated angiogenesis and tumor gsrowth. J Exp Med 2003;197:221–32

    Article  PubMed  CAS  Google Scholar 

  59. Yoshimoto A, Kasahara K, Kawashima A, Fujimura M, Nakao S. Characterization of the prostaglandin biosynthetic pathway in non-small cell lung cancer: a comparison with small cell lung cancer and correlation with angiogenesis, angiogenic factors and metastases. Oncol Rep 2005;13:1049–57

    PubMed  CAS  Google Scholar 

  60. Paget S. The distribution of secondary growths in cancer of the breast. Lancet 1889;1:571–3

    Article  Google Scholar 

  61. Maekawa M, Ishizaki T, Boku S, et al. Signaling from Rho to the actin cytoskeleton through protein kinases ROCK and LIM-kinase. Science 1999;285:895–8

    Article  PubMed  CAS  Google Scholar 

  62. Bretscher A, Edwards K, Fehon RG. ERM proteins and merlin: integrators at the cell cortex. Nat Rev Mol Cell Biol 2002;3:586–99

    Article  PubMed  CAS  Google Scholar 

  63. Creutz CE. The annexins and exocytosis. Science 1992;258:924–31

    Article  PubMed  CAS  Google Scholar 

  64. Wehrle-Haller B, Imhof B. The inner lives of focal adhesions. Trends Cell Biol 2002;12:382–9

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

The authors thank Kuan-Hua Chen, Chia-Li Lu and Li-Ling Yang for their excellent technical assistance. This work was supported by grants from the Taipei Veterans General Hospital (VGH93-64; Y-CW) and the Taiwan National Science Council (92-2314-B-039-009; C-TH).

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Authors and Affiliations

  1. Division of Thoracic Surgery, Department of Surgery, Taipei Veterans General Hospital and School of Medicine, National Yang-Ming University, 201, Sec 2, Shih-Pai Road, Taipei, 112, Taiwan

    Hao-Wei Wang MD, Wen-Hu Hsu MD, Liang-Shun Wang MD & Yu-Chung Wu MD

  2. Division of Hematology/Oncology, Department of Internal Medicine, University of Kansas Medical Center, 3901 Rainbow Boulevard, Kansas City, KS, 66160, USA

    Chung-Tsen Hsueh MD, PhD

  3. Department of Statistics, National Taipei University, 151 University Road, San Shia, Taipei, 237, Taiwan

    Chien-Fu Jeff Lin MD, PhD

  4. Department of Pathology, Taipei Veterans General Hospital and School of Medicine, National Yang-Ming University, 201, Sec 2, Shih-pai Road, Taipei, 112, Taiwan

    Teh-Ying Chou MD, PhD

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  1. Hao-Wei Wang MD
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Correspondence to Yu-Chung Wu MD.

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Wang, HW., Hsueh, CT., Lin, CF.J. et al. Clinical Implications of Microsomal Prostaglandin E Synthase-1 Overexpression in Human Non–Small-Cell Lung Cancer. Ann Surg Oncol 13, 1224–1234 (2006). https://doi.org/10.1245/s10434-006-9001-4

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