title: Areca nut contributes to oral malignancy through facilitating the conversion of cancer stem cells.
abstract: Oral cancer is one of the most frequent malignant diseases worldwide, and areca nut is a primary carcinogen causing this cancer in Southeast Asia. Previous studies to examine the effects of this carcinogen often used short-term and high-dose treatment of area nut extract as a research model, which do not recapitulate the conditions of patients with long-term and habitual use of this substance. To approach authentic mechanism of areca nut-induced oral carcinogenesis that occurs in human, we established four isogenic sublines of oral cells which were chronic exposed to areca nut extract. Without eliciting cytotoxicity or senescence, these four sublines cells exhibited significant increase in invasive ability, along with epithelial-mesenchymal transition. These cells also showed resistance to chemotherapeutic drug and irradiation, accompanying with the augmentation of ABCG2 protein efflux and increased ROS clearance. Moreover, these sublines possessed the characteristics of cancer stemness, as demonstrated by enriched CD24-/CD44+ and CD133+ sub-populations, enhanced spheroid cell formation, and induced expressions of pluripotent stemness regulators, including Gp96, Grp78, Slug, Sox9, Snail, and Foxc2. These stemness regulators were further shown up-regulations in oral cancer patients with areca nut-chewing habit, and were statistically correlated with CD44 expression, a stemness marker. In conclusion, our findings suggested that areca nut contributes to oral malignancy through facilitating the conversion of cancer stem cells. This study may further contribute to clinical applications in disease prevention, risk assessment or molecular therapeutics on areca nut- associated diseases.
authors.affiliation: Department of Medical Biotechnology, College of Medicine, Chang Gung University, Taoyuan, Taiwan.
authors.forename: Yi-Chen
authors.initials: YC
authors.lastname: Li
authors.affiliation: Department of Radiation Oncology, Chang Gung Memorial Hospital, Taoyuan, Taiwan.
authors.forename: Joseph T
authors.initials: JT
authors.lastname: Chang
authors.affiliation: Department of Medical Biotechnology, College of Medicine, Chang Gung University, Taoyuan, Taiwan.
authors.forename: Crystal
authors.initials: C
authors.lastname: Chiu
authors.affiliation: Department of Medical Biotechnology, College of Medicine, Chang Gung University, Taoyuan, Taiwan.
authors.forename: Ya-Ching
authors.initials: YC
authors.lastname: Lu
authors.affiliation: Department of Medical Biotechnology, College of Medicine, Chang Gung University, Taoyuan, Taiwan.
authors.forename: Yan-Liang
authors.initials: YL
authors.lastname: Li
authors.affiliation: Department of Medical Biotechnology, College of Medicine, Chang Gung University, Taoyuan, Taiwan.
authors.forename: Chang-Hsu
authors.initials: CH
authors.lastname: Chiang
authors.affiliation: Department of Medical Biotechnology, College of Medicine, Chang Gung University, Taoyuan, Taiwan.
authors.forename: Guo-Rung
authors.initials: GR
authors.lastname: You
authors.affiliation: Department of Pathology, Chang Gung Memorial Hospital, Taoyuan, Taiwan.
authors.forename: Li-Yu
authors.initials: LY
authors.lastname: Lee
authors.affiliation: Department of Medical Biotechnology, College of Medicine, Chang Gung University, Taoyuan, Taiwan.
authors.forename: Ann-Joy
authors.initials: AJ
authors.lastname: Cheng
mesh_terms: D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000378:metabolism; D001114:Areca / Q000737:chemistry*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D000091342:Endoplasmic Reticulum Chaperone BiP; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D009062:Mouth Neoplasms / Q000139:chemically induced* / Q000378:metabolism; D009363:Neoplasm Proteins / Q000378:metabolism; D014411:Neoplastic Stem Cells / Q000378:metabolism / Q000473:pathology*; D010936:Plant Extracts / Q000633:toxicity*; D017382:Reactive Oxygen Species / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects
chemical_list: C116614:ABCG2 protein, human; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D000091342:Endoplasmic Reticulum Chaperone BiP; C000717247:HSPA5 protein, human; D009363:Neoplasm Proteins; D010936:Plant Extracts; D017382:Reactive Oxygen Species
keywords: areca nut; cancer stem cell; carcinogenesis; invasion; oral cancer