Research Papers:

Areca nut components stimulate ADAM17, IL-1α, PGE2 and 8-isoprostane production in oral keratinocyte: role of reactive oxygen species, EGF and JAK signaling

Mei-Chi Chang, Chiu-Po Chan, Yi-Jane Chen, Hsiang-Chi Hsien, Ya-Ching Chang, Sin-Yuet Yeung, Po-Yuan Jeng, Ru-Hsiu Cheng, Liang-Jiunn Hahn and Jiiang-Huei Jeng _

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Oncotarget. 2016; 7:16879-16894. https://doi.org/10.18632/oncotarget.7621

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Mei-Chi Chang1,2, Chiu-Po Chan2, Yi-Jane Chen3, Hsiang-Chi Hsien2, Ya-Ching Chang4, Sin-Yuet Yeung2, Po-Yuan Jeng5, Ru-Hsiu Cheng3, Liang-Jiunn Hahn3, Jiiang-Huei Jeng3

1Team of Biomedical Science, Chang-Gung University of Science and Technology, Kwei-Shan, Taoyuan City, Taiwan

2Department of Dentistry, Chang Gung Memorial Hospital, Taipei, Taiwan

3Laboratory of Pharmacology, Toxicology and Chemical Carcinogenesis, School of Dentistry and Department of Dentistry, National Taiwan University Hospital and National Taiwan University Medical College, Taipei, Taiwan

4Department of Dentistry, Mackay Memorial Hospial, and Mackay Junior College of Medicine, Nursing and Management, Taipei, Taiwan

5School of Dentistry, University of Cardenal Herrera, CEU, Valencia, Spain

Correspondence to:

Jiiang-Huei Jeng, e-mail: jhjeng@ntu.edu.tw, benson86778231@yahoo.com.tw

Keywords: betel quid, oral cancer, epidermal growth factor, prostanoids, signal transduction

Received: November 15, 2015     Accepted: February 09, 2016     Published: February 23, 2016


Betel quid (BQ) chewing is an etiologic factor of oral submucous fibrosis (OSF) and oral cancer. There are 600 million BQ chewers worldwide. The mechanisms for the toxic and inflammatory responses of BQ are unclear. In this study, both areca nut (AN) extract (ANE) and arecoline stimulated epidermal growth factor (EGF) and interleukin-1α (IL-1α) production of gingival keratinocytes (GKs), whereas only ANE can stimulate a disintegrin and metalloproteinase 17 (ADAM17), prostaglandin E2 (PGE2) and 8-isoprostane production. ANE-induced EGF production was inhibited by catalase. Addition of anti-EGF neutralizing antibody attenuated ANE-induced cyclooxygenase-2 (COX-2), mature ADAM9 expression and PGE2 and 8-isoprostane production. ANE-induced IL-1α production was inhibited by catalase, anti-EGF antibody, PD153035 (EGF receptor antagonist) and U0126 (MEK inhibitor) but not by α-naphthoflavone (cytochrome p450-1A1 inhibitor). ANE-induced ADAM17 production was inhibited by pp2 (Src inhibitor), U0126, α-naphthoflavone and aspirin. AG490 (JAK inhibitor) prevented ANE-stimulated ADAM17, IL-1α, PGE2 production, COX-2 expression, ADAM9 maturation, and the ANE-induced decline in keratin 5 and 14, but showed little effect on cdc2 expression and EGF production. Moreover, ANE-induced 8-isoprostane production by GKs was inhibited by catalase, anti-EGF antibody, AG490, pp2, U0126, α-naphthoflavone, Zinc protoporphyrin (ZnPP) and aspirin. These results indicate that AN components may involve in BQ-induced oral cancer by induction of reactive oxygen species, EGF/EGFR, IL-1α, ADAMs, JAK, Src, MEK/ERK, CYP1A1, and COX signaling pathways, and the aberration of cell cycle and differentiation. Various blockers against ROS, EGF, IL-1α, ADAM, JAK, Src, MEK, CYP1A1, and COX can be used for prevention or treatment of BQ chewing-related diseases.

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