title: Acquisition cancer stemness, mesenchymal transdifferentiation, and chemoresistance properties by chronic exposure of oral epithelial cells to arecoline.
abstract: Oral squamous cell carcinoma (OSCC), one of the most deadliest malignancies in the world, is caused primarily by areca nut chewing in Southeast Asia. The mechanisms by which areca nut participates in OSCC tumorigenesis are not well understood. In this study, we investigated the effects of low dose long-term arecoline (10 μg/mL, 90-days), a major areca nut alkaloid, on enhancement cancer stemness of human oral epithelial (OE) cells. OE cells with chronic arecoline exposure resulted in increased ALDH1 population, CD44 positivity, stemness-related transcription factors (Oct4, Nanog, and Sox2), epithelial-mesenchymal transdifferentiation (EMT) traits, chemoresistance, migration/invasiveness/anchorage independent growth and in vivo tumor growth as compared to their untreated controls. Mechanistically, ectopic miR-145 over-expression in chronic arecoline-exposed OE (AOE) cells inhibited the cancer stemness and xenografic. In AOE cells, luciferase reporter assays further revealed that miR-145 directly targets the 3' UTR regions of Oct4 and Sox2 and overexpression of Sox2/Oct4 effectively reversed miR-145-regulated cancer stemness-associated phenomenas. Additionally, clinical results further revealed that Sox2 and Oct4 expression was inversely correlated with miR-145 in the tissues of areca quid chewing-associated OSCC patients. This study hence attempts to provide novel insight into areca nut-induced oral carcinogenesis and new intervention for the treatment of OSCC patients, especially in areca nut users.
authors.affiliation: School of Dentistry, Chung Shan Medical University, Taichung, Taiwan.
authors.forename: Tung Yuan
authors.initials: TY
authors.lastname: Wang
authors.affiliation: School of Dentistry, Chung Shan Medical University, Taichung, Taiwan.|Department of Dentistry, Chung Shan Medical University Hospital, Taichung, Taiwan.
authors.forename: Chih-Yu
authors.initials: CY
authors.lastname: Peng
authors.affiliation: School of Public Health, Chung Shan Medical University, Taichung, Taiwan.
authors.forename: Shiuan-Shinn
authors.initials: SS
authors.lastname: Lee
authors.affiliation: School of Dentistry, Chung Shan Medical University, Taichung, Taiwan.|Department of Dentistry, Chung Shan Medical University Hospital, Taichung, Taiwan.|Institute of Oral Sciences, Chung Shan Medical University, Taichung, Taiwan.
authors.forename: Ming-Yung
authors.initials: MY
authors.lastname: Chou
authors.affiliation: School of Dentistry, Chung Shan Medical University, Taichung, Taiwan.|Department of Dentistry, Chung Shan Medical University Hospital, Taichung, Taiwan.|Institute of Oral Sciences, Chung Shan Medical University, Taichung, Taiwan.
authors.forename: Cheng-Chia
authors.initials: CC
authors.lastname: Yu
authors.affiliation: School of Dentistry, Chung Shan Medical University, Taichung, Taiwan.|Department of Dentistry, Chung Shan Medical University Hospital, Taichung, Taiwan.
authors.forename: Yu-Chao
authors.initials: YC
authors.lastname: Chang
mesh_terms: D020413:3' Untranslated Regions; D000080924:Aldehyde Dehydrogenase 1 Family; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D001115:Arecoline / Q000633:toxicity*; D002294:Carcinoma, Squamous Cell / Q000139:chemically induced* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D002460:Cell Line; D002471:Cell Transformation, Neoplastic / Q000139:chemically induced* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D002945:Cisplatin / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm; D004847:Epithelial Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects*; D005472:Fluorouracil / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic; D006258:Head and Neck Neoplasms / Q000139:chemically induced* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D006801:Humans; D018960:Hyaluronan Receptors / Q000378:metabolism; D007527:Isoenzymes / Q000378:metabolism; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism; D009061:Mouth Mucosa / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D009062:Mouth Neoplasms / Q000139:chemically induced* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D000071317:Nanog Homeobox Protein / Q000235:genetics / Q000378:metabolism; D014411:Neoplastic Stem Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D050814:Octamer Transcription Factor-3 / Q000378:metabolism; D010641:Phenotype; D050697:Retinal Dehydrogenase / Q000378:metabolism; D055748:SOXB1 Transcription Factors / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D000077195:Squamous Cell Carcinoma of Head and Neck; D013997:Time Factors; D014162:Transfection
chemical_list: D020413:3' Untranslated Regions; D000970:Antineoplastic Agents; C497483:CD44 protein, human; D018960:Hyaluronan Receptors; D007527:Isoenzymes; C541010:MIRN145 microRNA, human; D035683:MicroRNAs; C486780:NANOG protein, human; D000071317:Nanog Homeobox Protein; D050814:Octamer Transcription Factor-3; C494173:POU5F1 protein, human; C527782:SOX2 protein, human; D055748:SOXB1 Transcription Factors; D001115:Arecoline; D000080924:Aldehyde Dehydrogenase 1 Family; C510223:ALDH1A1 protein, human; C515028:ALDH1A1 protein, mouse; D050697:Retinal Dehydrogenase; D002945:Cisplatin; D005472:Fluorouracil
keywords: arecoline; cancer stemness; oral squamous cell carcinomas