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Finnish Institute of Occupational Health [H. W., S. A., A. K.], 00250 Helsinki, and Departments of Obstetrics and Gynecology [K. S., A. R.] and Bacteriology and Immunology, the Haartman Institute [A. R.], University of Helsinki, 00290 Helsinki, Finland, and International Agency for Research on Cancer, Lyon, France [H. V.], F-69372 Lyon Cedex 08
Epidemiological studies indicate that the use of aspirin decreases incidence of and mortality from gastrointestinal cancers. A major target of aspirin and other nonsteroid anti-inflammatory drugs is cyclooxygenase (Cox), the rate-limiting enzyme in the conversion of arachidonic acid to prostanoids. Two Cox genes have been cloned (Cox-1 and Cox-2), of which Cox-2 has recently been found to be expressed in several human carcinomas. We have now studied the expression of Cox-2 mRNA and protein in human lung adenocarcinoma, squamous cell carcinoma, and small cell lung cancer. Cox-2 mRNA steady-state levels were high in well-differentiated adenocarcinoma samples, but low in poorly differentiated adenocarcinoma, squamous cell carcinoma, and small cell lung cancer, as detected by Northern blot analysis. Immunohistochemistry showed Cox-2 staining in 19 of 21 adenocarcinomas. However, well-differentiated adenocarcinomas contained more Cox-2 staining than the poorly differentiated ones. Expression of the Cox-2 protein was also seen in all 11 squamous cell carcinomas studied, although the level of staining seemed to be less than that in the adenocarcinomas. Small cell lung cancer specimens (n = 4) stained with a relatively weak intensity. Interestingly, atypical alveolar epithelium, which associates with asbestosis and idiopathic fibrosing alveolitis and is considered to be a precursor lesion for lung cancer, expressed the Cox-2 protein. Our data, thus, suggest that Cox-2 is expressed in human lung carcinomas and in precursor lesions leading to this malignancy.
1 Supported by the Finnish Institute of Occupational Health, Academy of Finland, Helsinki University Central Hospital Research Funds, and Clinical Research Institute of Helsinki University Central Hospital.
2 To whom requests for reprints should be addressed, at Laboratory of Pathology, Finnish Institute of Occupational Health, Topeliuksenkatu 41aA, 00250 Helsinki, Finland. Phone: 358-9-474-7282; Fax: 358-9-241-2414.
Received 7/15/98. Accepted 10/ 1/98.
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L. Ermert, C. Dierkes, and M. Ermert Immunohistochemical Expression of Cyclooxygenase Isoenzymes and Downstream Enzymes in Human Lung Tumors Clin. Cancer Res., May 1, 2003; 9(5): 1604 - 1610. [Abstract] [Full Text] [PDF]
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Y. Miyata, S. Koga, S. Kanda, M. Nishikido, T. Hayashi, and H. Kanetake Expression of Cyclooxygenase-2 in Renal Cell Carcinoma: Correlation with Tumor Cell Proliferation, Apoptosis, Angiogenesis, Expression of Matrix Metalloproteinase-2, and Survival Clin. Cancer Res., May 1, 2003; 9(5): 1741 - 1749. [Abstract] [Full Text] [PDF]
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H. A. Minter, J. W. Eveson, S. Huntley, D. J. E. Elder, and A. Hague The Cyclooxygenase 2-selective Inhibitor NS398 Inhibits Proliferation of Oral Carcinoma Cell Lines by Mechanisms Dependent and Independent of Reduced Prostaglandin E2 Synthesis Clin. Cancer Res., May 1, 2003; 9(5): 1885 - 1897. [Abstract] [Full Text] [PDF]
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H. Sawaoka, D. A. Dixon, J. A. Oates, and O. Boutaud Tristetraprolin Binds to the 3'-Untranslated Region of Cyclooxygenase-2 mRNA. A POLYADENYLATION VARIANT IN A CANCER CELL LINE LACKS THE BINDING SITE J. Biol. Chem., April 11, 2003; 278(16): 13928 - 13935. [Abstract] [Full Text] [PDF]
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 T. Inaba, H. Sano, Y. Kawahito, T. Hla, K. Akita, M. Toda, I. Yamashina, M. Inoue, and H. Nakada Induction of cyclooxygenase-2 in monocyte/macrophage by mucins secreted from colon cancer cells PNAS, March 4, 2003; 100(5): 2736 - 2741. [Abstract] [Full Text] [PDF]
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I. Milas, R. Komaki, T. Hachiya, R. S. Bubb, J. Y. Ro, L. Langford, R. Sawaya, J. B. Putnam, P. Allen, J. D. Cox, et al. Epidermal Growth Factor Receptor, Cyclooxygenase-2, and BAX Expression in the Primary Non-Small Cell Lung Cancer and Brain Metastases Clin. Cancer Res., March 1, 2003; 9(3): 1070 - 1076. [Abstract] [Full Text] [PDF]
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M. Dohadwala, R. K. Batra, J. Luo, Y. Lin, K. Krysan, M. Pold, S. Sharma, and S. M. Dubinett Autocrine/Paracrine Prostaglandin E2 Production by Non-small Cell Lung Cancer Cells Regulates Matrix Metalloproteinase-2 and CD44 in Cyclooxygenase-2-dependent Invasion J. Biol. Chem., December 20, 2002; 277(52): 50828 - 50833. [Abstract] [Full Text] [PDF]
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M. E. Reid, A. J. Duffield-Lillico, L. Garland, B. W. Turnbull, L. C. Clark, and J. R. Marshall Selenium Supplementation and Lung Cancer Incidence: An Update of the Nutritional Prevention of Cancer Trial Cancer Epidemiol. Biomarkers Prev., November 1, 2002; 11(11): 1285 - 1291. [Abstract] [Full Text] [PDF]
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 G E Goodman Lung cancer * 1: Prevention of lung cancer Thorax, November 1, 2002; 57(11): 994 - 999. [Abstract] [Full Text] [PDF]
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S. A. Wardlaw, N. Zhang, and S. A. Belinsky Transcriptional Regulation of Basal Cyclooxygenase-2 Expression in Murine Lung Tumor-Derived Cell Lines by CCAAT/Enhancer-Binding Protein and Activating Transcription Factor/cAMP Response Element-Binding Protein Mol. Pharmacol., August 1, 2002; 62(2): 326 - 333. [Abstract] [Full Text] [PDF]
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G. K. Dy and A. A. Adjei Novel Targets for Lung Cancer Therapy: Part II J. Clin. Oncol., July 1, 2002; 20(13): 3016 - 3028. [Abstract] [Full Text] [PDF]
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T. Hida, K.-i. Kozaki, H. Ito, O. Miyaishi, Y. Tatematsu, T. Suzuki, K. Matsuo, T. Sugiura, M. Ogawa, T. Takahashi, et al. Significant Growth Inhibition of Human Lung Cancer Cells Both in Vitro and in Vivo by the Combined Use of a Selective Cyclooxygenase 2 Inhibitor, JTE-522, and Conventional Anticancer Agents Clin. Cancer Res., July 1, 2002; 8(7): 2443 - 2447. [Abstract] [Full Text] [PDF]
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C Costa, R Soares, J S Reis-Filho, D Leitao, I Amendoeira, and F C Schmitt Cyclo-oxygenase 2 expression is associated with angiogenesis and lymph node metastasis in human breast cancer J. Clin. Pathol., June 1, 2002; 55(6): 429 - 434. [Abstract] [Full Text] [PDF]
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C. C. Sombroek, A. G. M. Stam, A. J. Masterson, S. M. Lougheed, M. J. A. G. Schakel, C. J. L. M. Meijer, H. M. Pinedo, A. J. M. van den Eertwegh, R. J. Scheper, and T. D. de Gruijl Prostanoids Play a Major Role in the Primary Tumor-Induced Inhibition of Dendritic Cell Differentiation J. Immunol., May 1, 2002; 168(9): 4333 - 4343. [Abstract] [Full Text] [PDF]
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 C. Denkert, M. Kobel, S. Pest, I. Koch, S. Berger, M. Schwabe, A. Siegert, A. Reles, B. Klosterhalfen, and S. Hauptmann Expression of Cyclooxygenase 2 Is an Independent Prognostic Factor in Human Ovarian Carcinoma Am. J. Pathol., March 1, 2002; 160(3): 893 - 903. [Abstract] [Full Text] [PDF]
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T. Niki, T. Kohno, S. Iba, Y. Moriya, Y. Takahashi, M. Saito, A. Maeshima, T. Yamada, Y. Matsuno, M. Fukayama, et al. Frequent Co-Localization of Cox-2 and Laminin-5 {gamma}2 Chain at the Invasive Front of Early-Stage Lung Adenocarcinomas Am. J. Pathol., March 1, 2002; 160(3): 1129 - 1141. [Abstract] [Full Text] [PDF]
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K. J. Sales, A. A. Katz, B. Howard, R. P. Soeters, R. P. Millar, and H. N. Jabbour Cyclooxygenase-1 Is Up-Regulated in Cervical Carcinomas: Autocrine/Paracrine Regulation of Cyclooxygenase-2, Prostaglandin E Receptors, and Angiogenic Factors by Cyclooxygenase-1 Cancer Res., January 1, 2002; 62(2): 424 - 432. [Abstract] [Full Text] [PDF]
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S. Zha, W. R. Gage, J. Sauvageot, E. A. Saria, M. J. Putzi, C. M. Ewing, D. A. Faith, W. G. Nelson, A. M. De Marzo, and W. B. Isaacs Cyclooxygenase-2 Is Up-Regulated in Proliferative Inflammatory Atrophy of the Prostate, but not in Prostate Carcinoma Cancer Res., December 1, 2001; 61(24): 8617 - 8623. [Abstract] [Full Text] [PDF]
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K. Yoshimatsu, D. Golijanin, P. B. Paty, R. A. Soslow, P.-J. Jakobsson, R. A. DeLellis, K. Subbaramaiah, and A. J. Dannenberg Inducible Microsomal Prostaglandin E Synthase Is Overexpressed in Colorectal Adenomas and Cancer Clin. Cancer Res., December 1, 2001; 7(12): 3971 - 3976. [Abstract] [Full Text] [PDF]
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 B. L. Upham and J. G. Wagner Toxicant-Induced Oxidative Stress in Cancer Toxicol. Sci., November 1, 2001; 64(1): 1 - 3. [Abstract] [Full Text] [PDF]
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 E. Fritsche, S. J. Baek, L. M. King, D. C. Zeldin, T. E. Eling, and D. A. Bell Functional Characterization of Cyclooxygenase-2 Polymorphisms J. Pharmacol. Exp. Ther., November 1, 2001; 299(2): 468 - 476. [Abstract] [Full Text] [PDF]
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 K. Salmenkivi, C. Haglund, A. Ristimaki, J. Arola, and P. Heikkila Increased Expression of Cyclooxygenase-2 in Malignant Pheochromocytomas J. Clin. Endocrinol. Metab., November 1, 2001; 86(11): 5615 - 5619. [Abstract] [Full Text] [PDF]
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A. H. Klimp, H. Hollema, C. Kempinga, A. G. J. van der Zee, E. G. E. de Vries, and T. Daemen Expression of Cyclooxygenase-2 and Inducible Nitric Oxide Synthase in Human Ovarian Tumors and Tumor-associated Macrophages Cancer Res., October 1, 2001; 61(19): 7305 - 7309. [Abstract] [Full Text] [PDF]
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J. M. Kurie and R. N. Dubois Prostaglandin E Synthase: Another Enzyme in the Cyclooxygenase Pathway Driving Epithelial Cancer? Clin. Cancer Res., September 1, 2001; 7(9): 2608 - 2610. [Full Text] [PDF]
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K. Yoshimatsu, N. K. Altorki, D. Golijanin, F. Zhang, P.-J. Jakobsson, A. J. Dannenberg, and K. Subbaramaiah Inducible Prostaglandin E Synthase Is Overexpressed in Non-Small Cell Lung Cancer Clin. Cancer Res., September 1, 2001; 7(9): 2669 - 2674. [Abstract] [Full Text] [PDF]
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 E. M. P. de Almeida, C. Piche, J. Sirois, and M. Dore Expression of Cyclo-oxygenase-2 in Naturally Occurring Squamous Cell Carcinomas in Dogs J. Histochem. Cytochem., July 1, 2001; 49(7): 867 - 876. [Abstract] [Full Text] [PDF]
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K. J. Sales, A. A. Katz, M. Davis, S. Hinz, R. P. Soeters, M. D. Hofmeyr, R. P. Millar, and H. N. Jabbour Cyclooxygenase-2 Expression and Prostaglandin E2 Synthesis Are Up-Regulated in Carcinomas of the Cervix: A Possible Autocrine/Paracrine Regulation of Neoplastic Cell Function via EP2/EP4 Receptors J. Clin. Endocrinol. Metab., May 1, 2001; 86(5): 2243 - 2249. [Abstract] [Full Text]
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R. N. DuBois Cyclooxygenease-2 and Hepatocellular Carcinoma: Is It a Target for Prevention? Clin. Cancer Res., May 1, 2001; 7(5): 1110 - 1110. [Full Text]
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 K. Subbaramaiah, P. Bulic, Y. Lin, A. J. Dannenberg, and D. S. Pasco Development and Use of a Gene Promoter-Based Screen to Identify Novel Inhibitors of Cyclooxygenase-2 Transcription J Biomol Screen, April 1, 2001; 6(2): 101 - 110. [Abstract] [PDF]
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F. R. Khuri, H. Wu, J. J. Lee, B. L. Kemp, R. Lotan, S. M. Lippman, L. Feng, W. K. Hong, and X.-C. Xu Cyclooxygenase-2 Overexpression Is a Marker of Poor Prognosis in Stage I Non-Small Cell Lung Cancer Clin. Cancer Res., April 1, 2001; 7(4): 861 - 867. [Abstract] [Full Text]
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T. Shirahama and C. Sakakura Overexpression of Cyclooxygenase-2 in Squamous Cell Carcinoma of the Urinary Bladder Clin. Cancer Res., March 1, 2001; 7(3): 558 - 561. [Abstract] [Full Text]
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A. Ristimaki, O. Nieminen, K. Saukkonen, K. Hotakainen, S. Nordling, and C. Haglund Expression of Cyclooxygenase-2 in Human Transitional Cell Carcinoma of the Urinary Bladder Am. J. Pathol., March 1, 2001; 158(3): 849 - 853. [Abstract] [Full Text] [PDF]
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F. W. Wiese, P. A. Thompson, and F. F. Kadlubar Carcinogen substrate specificity of human COX-1 and COX-2 Carcinogenesis, January 1, 2001; 22(1): 5 - 10. [Abstract] [Full Text] [PDF]
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 S Chariyalertsak, V Sirikulchayanonta, D Mayer, A Kopp-Schneider, G Furstenberger, F Marks, and K Muller-Decker Aberrant cyclooxygenase isozyme expression in human intrahepatic cholangiocarcinoma Gut, January 1, 2001; 48(1): 80 - 86. [Abstract] [Full Text] [PDF]
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C. Denkert, M. Köbel, S. Berger, A. Siegert, A. Leclere, U. Trefzer, and S. Hauptmann Expression of Cyclooxygenase 2 in Human Malignant Melanoma Cancer Res., January 1, 2001; 61(1): 303 - 308. [Abstract] [Full Text]
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