Carcinogenesis Advance Access published online on May 22, 2003
Carcinogenesis, doi:10.1093/carcin/bgg083
© 2003 by Oxford University Press
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CANCER BIOLOGY
1 Laboratory of Dental Pharmacology & Toxicology, Department of Dentistry, National Taiwan University Hospital and National Taiwan University College of Medicine
* Corresponding author. E-mail: mcchang{at}mail.cgit.edu.tw.
Received 29 July 2002
; revised 10 March 2003
; accepted 29 April 2003
Betel quid (BQ) chewing is an etiologic factor of oral cancer and submucous fibrosis (OSF). Keratinocyte inflammation is crucial for the pathogenesis of cancer and tissue fibrosis. We found that AN extract (100-400 µg/ml) induced PGE2 production of KB cells by 2.34 to 23.1-fold and also the TNF-
Roles of keratinocyte inflammation in oral cancer: regulating the prostaglandin E2, interleukin-6 and TNF-
production of oral epithelial cells by areca nut extract and arecoline
2 Graduate Institute of Environmental Medicine, National Cheng-Kung University
3 Department of Pediatrics, National Taiwan University Hospital and Graduate Institute of Clinical Medicine, National Taiwan University
4 Department of Dentistry, Chang-Gung Memorial Hospital, Taipei
5 Department of Biomedical Technology, Taipei Medical College
6 Team of Biomedical Science, Chang-Gung Institute of Technology
production of gingival keratinocytes (GK). Arecoline (0.2-1.2 mM) elevated PGE2 production of KB cells by 2.5- to 6.1-fold. AN extract (200-400 µg/ml) also induced IL-6 production of GK (7.5 to 8.4-fold) and KB cells. Contrastingly, arecoline (0.1-1.2 mM) suppressed IL-6 production of GK and KB cells, with 42-81% and 41-63% of inhibition, respectively. A 48-h exposure of GK to 800-1200 µg/ml of AN extract led to 37%-69% of cell death. Arecoline cytotoxicity to GK was noted at concentrations of 0.8 to 1.2 mM, which led to 28%-38% of cell death. AN extract (400-800 µg/ml) induced Cox-2 and IL-6 mRNA expression and also COX-2 protein production of KB cells. IL-6 (5-100 ng/ml) suppressed GK growth by 20-33%, but enhanced oral fibroblasts (OMF) and KB cell growth. PGE2 (0.05-5 µg/ml) and IL-6 antibody (aby, 50-1000 ng/ml) showed little effect on GK and KB cell growth. Incubation of GK and KB cells to aspirin, IL-6 aby and TNF- aby showed little effect on arecoline- and AN-induced cytotoxicity, cell cycle arrest and apoptosis. Further, exposure to TNF- aby slightly affected the arecoline- and AN-modulated PGE2 and IL-6 production of GK and KB cells. Arecoline- and AN-conditioned medium decreased the phytoagglutinin-mediated CD4+ and CD8+ T cell activation of peripheral blood mononuclear cells. These results indicate that BQ chewing contributes to the pathogenesis of cancer and OSF by impairing T cell activation and by induction of PGE2, TNF- and IL-6 production, which affect oral mucosal inflammation and growth of OMF and oral epithelial cells.
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