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Areca nut exposure increases secretion of tumor-promoting cytokines in gingival fibroblasts that trigger DNA damage in oral keratinocytes

 Rasika P. Illeperuma  ;  Do Kyeong Kim  ;  Young Jin Park  ;  Hwa Kyung Son  ;  Jue Young Kim  ;  Jinmi Kim  ;  Doo Young Lee  ;  Ki-Yeol Kim  ;  Da-Woon Jung  ;  Wanninayake M. Tilakaratne  ;  Jin Kim 
 INTERNATIONAL JOURNAL OF CANCER, Vol.137(11) : 2545-2557, 2015 
Journal Title
Issue Date
Antioxidants/pharmacology ; Areca/adverse effects* ; Carcinogenesis/drug effects ; Carcinogenesis/metabolism ; Carcinogenesis/pathology ; Cells, Cultured ; DNA Breaks, Double-Stranded/drug effects ; DNA Damage/drug effects* ; Fibroblasts/drug effects* ; Fibroblasts/metabolism ; Fibroblasts/pathology ; Gingiva/drug effects* ; Gingiva/metabolism ; Gingiva/pathology ; HEK293 Cells ; Humans ; Interleukin-6/metabolism* ; Interleukin-8/metabolism* ; Keratinocytes/drug effects* ; Keratinocytes/metabolism ; Keratinocytes/pathology ; Mouth Mucosa/drug effects ; Mouth Mucosa/metabolism ; Mouth Mucosa/pathology ; NADPH Oxidase 1 ; NADPH Oxidase 4 ; NADPH Oxidases/metabolism ; Nuts/adverse effects ; Oral Submucous Fibrosis/metabolism ; Oral Submucous Fibrosis/pathology ; Reactive Oxygen Species/metabolism
DNA damage ; carcinogenesis ; cytokines ; fibroblasts ; oral submucous fibrosis
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.
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5. Research Institutes (연구소) > Oral Cancer Research Institute (구강종양연구소) > 1. Journal Papers
2. College of Dentistry (치과대학) > Dept. of Oral Pathology (구강병리학교실) > 1. Journal Papers
Yonsei Authors
Kim, Ki Yeol(김기열) ORCID logo https://orcid.org/0000-0001-5357-1067
Kim, Jin(김진)
Park, Young Jin(박영진)
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