FHIT is up-regulated by inflammatory stimuli and inhibits prostaglandin E2-mediated cancer progression

Koshi Mimori, Hideshi Ishii, Hisashi Nagahara, Tomoya Sudo, Keishi Yamashita, Hiroshi Inoue, Graham F. Barnard, Masaki Mori

Research output: Contribution to journalArticle

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Abstract

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.

Original languageEnglish
Pages (from-to)2683-2690
Number of pages8
JournalCancer Research
Volume66
Issue number5
DOIs
Publication statusPublished - Mar 1 2006

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Cyclooxygenase 2
Dinoprostone
Colorectal Neoplasms
Neoplasms
Epidermal Growth Factor Receptor
Cell Proliferation
Environmental Carcinogens
Cell Line
Small Interfering RNA
Enzyme-Linked Immunosorbent Assay
Immunohistochemistry
Inflammation
Phenotype
Genes

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

Cite this

FHIT is up-regulated by inflammatory stimuli and inhibits prostaglandin E2-mediated cancer progression. / Mimori, Koshi; Ishii, Hideshi; Nagahara, Hisashi; Sudo, Tomoya; Yamashita, Keishi; Inoue, Hiroshi; Barnard, Graham F.; Mori, Masaki.

In: Cancer Research, Vol. 66, No. 5, 01.03.2006, p. 2683-2690.

Research output: Contribution to journalArticle

Mimori, Koshi ; Ishii, Hideshi ; Nagahara, Hisashi ; Sudo, Tomoya ; Yamashita, Keishi ; Inoue, Hiroshi ; Barnard, Graham F. ; Mori, Masaki. / FHIT is up-regulated by inflammatory stimuli and inhibits prostaglandin E2-mediated cancer progression. In: Cancer Research. 2006 ; Vol. 66, No. 5. pp. 2683-2690.
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abstract = "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.",
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AU - Ishii, Hideshi

AU - Nagahara, Hisashi

AU - Sudo, Tomoya

AU - Yamashita, Keishi

AU - Inoue, Hiroshi

AU - Barnard, Graham F.

AU - Mori, Masaki

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AB - 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.

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