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FHIT Is Up-Regulated by Inflammatory Stimuli and Inhibits Prostaglandin E₂–Mediated Cancer Progression

¹ Department of Surgical Oncology, Medical Institute of Bioregulation, Kyushu University, Beppu, Japan; ² Division of Stem Cell Regulation/Molecular Hematopoiesis, Jichi Medical School, Center for Molecular Medicine, Tochigi, Japan; and ³ Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, Worcester, Massachusetts

Requests for reprints: Masaki Mori, FACS Department of Surgical Oncology, Medical Institute of Bioregulation, Kyushu University, 4546 Tsurumihara, Beppu 874-0838, Oita, Japan. Phone: 81-977-27-1650; Fax: 81-977-27-1651; E-mail: mmori{at}beppu.kyushu-u.ac.jp.

The FHIT gene is known to be susceptible to environmental carcinogens. Formation of prostaglandin E₂ (PGE₂) is catalyzed by cyclooxygenase-2 (COX-2) and may influence malignant phenotype in colorectal cancer. We explored whether FHIT might play a role in progression of colorectal cancer through inflammation-associated PGE₂ activity. Immunohistochemical study of COX-2 and FHIT expression was done in 92 colorectal cancer tumors. We also used a FHIT-expressing cancer cell line (H460) induced by ponasterone A and two FHIT small interfering RNA–treated colorectal cancer cell lines (CCK81 and DLD1). After PGE₂ stimulation, we compared synthesis of PGE₂ (ELISA assay) and cell proliferation [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay]. Immunohistochemistry showed a significant association between COX-2 and FHIT expression in colorectal cancers (P < 0.01). In a subset of 41 COX-2–expressing tumors, 12 FHIT^– tumors showed deeper cancer invasion than 29 FHIT⁺ tumors (P < 0.01). Experimental study, however, showed there was no direct interaction between FHIT and COX-2. Considered with results from another experiment with epidermal growth factor receptor (EGFR), we hypothesize that FHIT and COX-2 might be regulated by a common molecule, such as EGFR. Additionally, there was an inverse and direct correlation between PGE₂ synthesis and FHIT in vitro, suggesting that FHIT's postulated antiaggressive effect on tumor goes through PGE₂ but not COX-2. Loss of FHIT expression in colorectal cancer suggests higher malignant potential. We conclude that FHIT suppressed cancer cell proliferation in this malignancy by directly inhibiting synthesis of PGE₂ but not affecting that of COX-2. (Cancer Res 2006; 66(5): 2683-90)