Abstract
AimsChewing of betel quid (BQ) increases the risk of oral cancer and oral submucous fibrosis (OSF), possibly by BQ-induced toxicity and induction of inflammatory response in oral mucosa.MethodsPrimary gingival keratinocytes (GK cells) were exposed to areca nut (AN) components with/without inhibitors. Cytotoxicity was measured by 3-(4,5-dimethyl- thiazol- 2-yl)-2,5-diphenyl-tetrazolium bromide (MTT) assay. mRNA and protein expression was evaluated by reverse transcriptase-polymerase chain reaction (RT-PCR) and western blotting. PGE2/PGF2α production was measured by enzyme-linked immunosorbent assays.ResultsAreca nut extract (ANE) stimulated PGE2/PGF2α production, and upregulated the expression of cyclooxygenase-2 (COX-2), cytochrome P450 1A1 (CYP1A1) and hemeoxygenase-1 (HO-1), but inhibited expression of keratin 5/14, cyclinB1 and cdc25C in GK cells. ANE also activated epidermal growth factor receptor (EGFR), Src and Ras signaling pathways. ANE-induced COX-2, keratin 5, keratin 14 and cdc25C expression as well as PGE2 production were differentially regulated by α–naphthoflavone (a CYP 1A1/1A2 inhibitor), PD153035 (EGFR inhibitor), pp2 (Src inhibitor), and manumycin A (a Ras inhibitor). ANE-induced PGE2 production was suppressed by piper betle leaf (PBL) extract and hydroxychavicol (two major BQ components), dicoumarol (a NAD(P)H:Quinone Oxidoreductase - NQO1 inhibitor) and curcumin. ANE-induced cytotoxicity was inhibited by catalase and enhanced by dicoumarol, suggesting that AN components may contribute to the pathogenesis of OSF and oral cancer via induction of aberrant differentiation, cytotoxicity, COX-2 expression, and PGE2/PGF2αproduction.ConclusionsCYP4501A1, reactive oxygen species (ROS), EGFR, Src and Ras signaling pathways could all play a role in ANE-induced pathogenesis of oral cancer. Addition of PBL into BQ and curcumin consumption could inhibit the ANE-induced inflammatory response.
Highlights
Oral leukoplakia, oral submucous fibrosis (OSF) and oral cancer are popular diseases in India, Taiwan, Sri Lanka and many other south-east Asian countries where betel quid (BQ) chewing is popular [1,2,3]
To further understand the chemical carcinogenesis of BQ chewing-related cancer, we proposed that BQ can be metabolized by cytochrome P450 (CYP) to generate reactive oxygen species (ROS) and activate epidermal growth factor receptor (EGFR), Src, and Ras signaling pathways to stimulate COX-2 expression, prostanoids production and affect the differentiation of gingival keratinocytes (GK)
Effect of BQ Components on the Cytotoxicity and Prostanoids Production of GK Retraction and vacuoles formation of GK were noted after exposure to Areca nut extract (ANE) for 24-h
Summary
Oral submucous fibrosis (OSF) and oral cancer are popular diseases in India, Taiwan, Sri Lanka and many other south-east Asian countries where betel quid (BQ) chewing is popular [1,2,3]. Chemical carcinogenesis is a multi-step processes including initiation, promotion and progression, where genetic (DNA damage) and epigenetic alterations (histone acetylation, tissue inflammation etc.) are involved [2,4]. ROS production and tissue inflammation may further contribute to the carcinogenic processes by inducing more DNA damage, cell cycle arrest, aberrant differentiation, changes of signal transduction pathways, and thereby OSF and clinical tumors as observed in BQ chewers [5]. Epidermal growth factor receptor (EGFR), Src and Ras activation are possible molecular factors for chemical carcinogenesis [6,7,8]. Their roles in the pathogenesis of BQ chewing-related oral mucosal diseases are still obscure
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