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(Chest. 2002;121:29S-30S.)
© 2002 American College of Chest Physicians

Microarray Identifies Cyclo-oxygenase-2–Dependent Modulation of Insulin-like Growth Factor Binding Protein-3 in Non-small Cell Lung Cancer Cells*

Mehis Põld, MD; M. Dohadwala, PhD, MD; J. Luo; Y. Lin, MD and S. Dubinett, MD

* From the Division of Pulmonary and Critical Care Medicine, Jonsson Comprehensive Cancer Center, UCLA School of Medicine, Los Angeles, CA.

Correspondence to: Mehis Pold, MD, Dubinett’s Lab, Division of Pulmonary Medicine, 10833 LeComte Ave, Room 37–131, CHS, Los Angeles, CA 90095; e-mail: mpold{at}mednet.ucla.edu

Cyclo-oxygenase (COX)-2 is frequently overexpressed in non-small cell lung cancer (NSCLC). Previous studies have implicated a number of cytokines and growth factors in the regulation of COX-2 expression, and COX-2 itself modulates the expression of a variety of genes.1 2 3 4 5 Our previous studies show that prostaglandin E2, the major product of COX-2 activity, suppresses the T-cell–mediated immunity in lung cancer.6 7 In addition to its effects on cell-mediated immunity, tumor overexpression of COX-2 appears to be involved in enhanced invasion, promotion of angiogenesis, and resistance to apoptosis.8 9 10 11 Thus, there is mounting evidence indicating the importance of COX-2 in NSCLC. However, the knowledge about the changes in gene expression caused by the overexpression of COX-2 in NSCLC is fragmentary. In order to elucidate the COX-2–induced changes in NSCLC, we have conducted a microarray study using the Human Cancer Specific GeneChip (Affymetrix; Santa Clara, CA). In our study, we compared the expression of approximately 1,700 genes in the human lung adenocarcinoma cell line A549, transduced with COX-2, to A549 cells with either no or very little COX-2 expression. As a result, we have determined that the A549 cells of high COX-2 content express lower levels of insulin-like growth factor binding protein (IGFBP)-3 messenger RNA and, as determined by IGFBP-3 enzyme-linked immunosorbent assay, lower levels of free soluble IGFBP-3 protein. Thus, the amount of free soluble A549 inversely correlated with the expression level of COX-2. Previous studies have shown that IGFBP-3 antagonizes the mitogenicity of insulin-like growth factor (IGF)-1 and IGF-2.12 13 In addition, IGFBP-3 also has an IGF-independent tumor suppressor activity.14 15 16 Therefore, we hypothesize that COX-2–induced suppression of IGFBP-3 in lung cancer cells is one of the elements leading to increased tumorigenicity. This is the first study to implicate IGFBP-3 as a gene modulated by COX-2 overexpression in cancer cells.


   Footnotes
 
Abbreviations: COX = cyclo-oxgenase; IGF = insulin-like growth factor; IGFBP = insulin-like growth factor binding protein; NSCLC = non-small cell lung cancer


   References
TOP
 References
 

  1. Hayashi, Y, Kobayashi, M, Kuwata, H, et al (2000) Interferon-{gamma} and interleukin 4 inhibit interleukin 1 beta-induced delayed prostaglandin E(2) generation through suppression of cyclooxygenase-2 expression in human fibroblasts. Cytokine 12,603-612[CrossRef][ISI][Medline]
  2. Huang, ZF, Massey, JB, Via, DP (2000) Differential regulation of cyclo-oxygenase-2 (COX-2) mRNA stability by interleukin-1 ß (IL-1 ß) and tumor necrosis factor-{alpha} (TNF-{alpha}) in human in vitro differentiated macrophages. Biochem Pharmacol 59,187-194[CrossRef][ISI][Medline]
  3. Saha, D, Datta, PK, Sheng, H, et al (1999) Synergistic induction of cyclo-oxygenase-2 by transforming growth factor-ß1 and epidermal growth factor inhibits apoptosis in epithelial cells. Neoplasia 6,508-517
  4. Fong, CY, Pang, L, Holland, E, et al (2000) TGF-ß1 stimulates IL-8 release, COX-2 expression, and PGE(2) release in human airway smooth muscle cells. Am J Physiol Lung Cell Mol Physiol 279,201-207
  5. Sato, T, Nakajima, H, Fujio, K, et al (1997) Enhancement of prostaglandin E2 production by epidermal growth factor requires the coordinate activation of cytosolic phospholipase A2 and cyclo-oxygenase-2 in human squamous carcinoma A431 cells. Prostaglandins 53,355-369[CrossRef][ISI][Medline]
  6. Stolina, M, Sharma, S, Lin, Y, et al (2000) Specific inhibition of cyclo-oxygenase-2 restores antitumor reactivity by altering the balance of IL-10 and IL-12 synthesis. J Immunol 164,361-370[Abstract/Free Full Text]
  7. Huang, M, Stolina, M, Sharma, S, et al (1998) Non-small cell lung cancer cyclo-oxygenase-2-dependent regulation of cytokine balance in lymphocytes and macrophages: up-regulation of interleukin-10 and down-regulation of interleukin-12 production. Cancer Res 58,1208-1216[Abstract/Free Full Text]
  8. Tsujii, M, DuBois, RN (1995) Alterations in cellular adhesion and apoptosis in epithelial cells overexpressing prostaglandin endoperoxide synthase 2. Cell 83,493-501[CrossRef][ISI][Medline]
  9. Ding, XZ, Tong, WG, Adrian, TE (2000) Blockade of cyclo-oxygenase-2 inhibits proliferation and induces apoptosis in human pancreatic cancer cells. Anticancer Res 20,2625-2631[ISI][Medline]
  10. Masferrer, JL, Leahy, KM, Koki, AT, et al (2000) Antiangiogenic and antitumor activities of cyclo-oxygenase-2 inhibitors. Cancer Res 60,1306-1311[Abstract/Free Full Text]
  11. Liu, XH, Kirschenbaum, A, Yao, S, et al (2000) Inhibition of cyclo-oxygenase-2 suppresses angiogenesis and the growth of prostate cancer in vivo. J Urol 164,820-825[CrossRef][ISI][Medline]
  12. Grimberg, A, Cohen, P (2000) Role of insulin-like growth factors and their binding proteins in growth control and carcinogenesis. J Cell Physiol 183,1-9[CrossRef][ISI][Medline]
  13. Baxter, RC (2000) Insulin-like growth factor (IGF)-binding proteins: interactions with IGFs and intrinsic bioactivities. Am J Physiol Endocrinol Metab 278,967-976
  14. Butt, AJ, Firth, SM, King, MA, et al (2000) Insulin-like growth factor-binding protein-3 modulates expression of Bax and Bcl-2 and potentiates p53-independent radiation-induced apoptosis in human breast cancer cells. J Biol Chem 275,39174-39181[Abstract/Free Full Text]
  15. Hochscheid, R, Jaques, G, Wegmann, B (2000) Transfection of human insulin-like growth factor-binding protein-3 gene inhibits cell growth and tumorigenicity: a cell culture model for lung cancer. J Endocrinol 166,553-563[Abstract]
  16. Williams, AC, Collard, TJ, Perks, CM, et al (2000) Increased p53-dependent apoptosis by the insulin-like growth factor binding protein IGFBP-3 in human colonic adenoma-derived cells. Cancer Res 60,22-27[Abstract/Free Full Text]




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