title: Areca nut exposure increases secretion of tumor-promoting cytokines in gingival fibroblasts that trigger DNA damage in oral keratinocytes.
abstract: Molecular crosstalk between cancer cells and fibroblasts has been an emerging hot issue in understanding carcinogenesis. As oral submucous fibrosis (OSF) is an inflammatory fibrotic disease that can potentially transform into squamous cell carcinoma, OSF has been considered to be an appropriate model for studying the role of fibroblasts during early stage carcinogenesis. In this sense, this study aims at investigating whether areca nut (AN)-exposed fibroblasts cause DNA damage of epithelial cells. For this study, immortalized hNOF (hTERT-hNOF) was used. We found that the levels of GRO-α, IL-6 and IL-8 increased in AN-exposed fibroblasts. Cytokine secretion was reduced by antioxidants in AN-exposed fibroblasts. Increase in DNA double strand breaks (DSB) and 8-oxoG FITC-conjugate was observed in immortalized human oral keratinocytes (IHOK) after the treatment of cytokines or a conditioned medium derived from AN-exposed fibroblasts. Cytokine expression and DNA damage were also detected in OSF tissues. The DNA damage was reduced by neutralizing cytokines or antioxidant treatment. Generation of reactive oxygen species (ROS) and DNA damage response, triggered by cytokines, were abolished when NADPH oxidase (NOX) 1 and 4 were silenced in IHOK, indicating that cytokine-triggered DNA damage was caused by ROS generation through NOX1 and NOX4. Taken together, this study provided strong evidence that blocking ROS generation might be a rewarding approach for cancer prevention and intervention in OSF.
authors.affiliation: Oral Cancer Research Institute, Department of Oral Pathology, Yonsei University College of Dentistry, Seoul, Korea.|Faculty of Allied Health Sciences, Department of Medical Laborotary Science, University of Peradeniya, Sri Lanka.
authors.forename: Rasika P
authors.initials: RP
authors.lastname: Illeperuma
authors.affiliation: Oral Cancer Research Institute, Department of Oral Pathology, Yonsei University College of Dentistry, Seoul, Korea.|BK 21 PLUS Project, Yonsei University College of Dentistry, Seoul, Korea.
authors.forename: Do Kyeong
authors.initials: DK
authors.lastname: Kim
authors.affiliation: Oral Cancer Research Institute, Department of Oral Pathology, Yonsei University College of Dentistry, Seoul, Korea.|BK 21 PLUS Project, Yonsei University College of Dentistry, Seoul, Korea.
authors.forename: Young Jin
authors.initials: YJ
authors.lastname: Park
authors.affiliation: Oral Cancer Research Institute, Department of Oral Pathology, Yonsei University College of Dentistry, Seoul, Korea.|Department of Dental Hygiene, Yeungnam University College, Daegu, Korea.
authors.forename: Hwa Kyung
authors.initials: HK
authors.lastname: Son
authors.affiliation: Oral Cancer Research Institute, Department of Oral Pathology, Yonsei University College of Dentistry, Seoul, Korea.|BK 21 PLUS Project, Yonsei University College of Dentistry, Seoul, Korea.
authors.forename: Jue Young
authors.initials: JY
authors.lastname: Kim
authors.affiliation: Oral Cancer Research Institute, Department of Oral Pathology, Yonsei University College of Dentistry, Seoul, Korea.
authors.forename: Jinmi
authors.initials: J
authors.lastname: Kim
authors.affiliation: Oral Cancer Research Institute, Department of Oral Pathology, Yonsei University College of Dentistry, Seoul, Korea.
authors.forename: Doo Young
authors.initials: DY
authors.lastname: Lee
authors.affiliation: Oral Cancer Research Institute, Department of Oral Pathology, Yonsei University College of Dentistry, Seoul, Korea.
authors.forename: Ki-Yeol
authors.initials: KY
authors.lastname: Kim
authors.affiliation: Department of Life Sciences, Gwangju Institute of Science and Technology, Gwangju, Korea.
authors.forename: Da-Woon
authors.initials: DW
authors.lastname: Jung
authors.affiliation: Faculty of Dental Sciences, Department of Oral Pathology, University of Peradeniya, Sri Lanka.
authors.forename: Wanninayake M
authors.initials: WM
authors.lastname: Tilakaratne
authors.affiliation: Oral Cancer Research Institute, Department of Oral Pathology, Yonsei University College of Dentistry, Seoul, Korea.|BK 21 PLUS Project, Yonsei University College of Dentistry, Seoul, Korea.
authors.forename: Jin
authors.initials: J
authors.lastname: Kim
mesh_terms: D000975:Antioxidants / Q000494:pharmacology; D001114:Areca / Q000009:adverse effects*; D063646:Carcinogenesis / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D002478:Cells, Cultured; D053903:DNA Breaks, Double-Stranded / Q000187:drug effects; D004249:DNA Damage / Q000187:drug effects*; D005347:Fibroblasts / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D005881:Gingiva / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D057809:HEK293 Cells; D006801:Humans; D015850:Interleukin-6 / Q000378:metabolism*; D016209:Interleukin-8 / Q000378:metabolism*; D015603:Keratinocytes / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D009061:Mouth Mucosa / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D000074624:NADPH Oxidase 1; D000074663:NADPH Oxidase 4; D019255:NADPH Oxidases / Q000378:metabolism; D009754:Nuts / Q000009:adverse effects; D009914:Oral Submucous Fibrosis / Q000378:metabolism / Q000473:pathology; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D000975:Antioxidants; D015850:Interleukin-6; D016209:Interleukin-8; D017382:Reactive Oxygen Species; D000074624:NADPH Oxidase 1; D000074663:NADPH Oxidase 4; D019255:NADPH Oxidases; C402799:NOX1 protein, human; C498910:NOX4 protein, human
keywords: DNA damage; carcinogenesis; cytokines; fibroblasts; oral submucous fibrosis