J Cancer 2019; 10(17):4054-4062. doi:10.7150/jca.29765 This issue

Review

Multifaceted Mechanisms of Areca Nuts in Oral Carcinogenesis: the Molecular Pathology from Precancerous Condition to Malignant Transformation

Yi-Chen Li1*, Ann-Joy Cheng2,3*, Li-Yu Lee4, Yu-Chen Huang5, Joseph Tung-Chieh Chang3,6,✉

1. Division of Cardiology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 833, Taiwan.
2. Department of Medical Biotechnology and Laboratory Science, College of Medicine, Chang Gung University, Taoyuan 333, Taiwan
3. Department of Radiation Oncology, Chang Gung Memorial Hospital-Linkou, Taoyuan 333, Taiwan
4. Department of Pathology, Chang Gung Memorial Hospital-Linkou, Taoyuan 333, Taiwan
5. Department of Oral Maxillofacial Surgery, Chang Gung Memorial Hospital-Linkou, Taoyuan 333, Taiwan
6. Department of Radiation Oncology, Xiamen Chang Gung Memorial Hospital, Xiamen, Fujian, China
*First and second authors contributed equally

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Citation:
Li YC, Cheng AJ, Lee LY, Huang YC, Chang JTC. Multifaceted Mechanisms of Areca Nuts in Oral Carcinogenesis: the Molecular Pathology from Precancerous Condition to Malignant Transformation. J Cancer 2019; 10(17):4054-4062. doi:10.7150/jca.29765. Available from https://www.jcancer.org/v10p4054.htm

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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. It has been widely reported that areca nut induced several cytotoxic effects in oral cells, including ROS generation, inflammation, tissue hypoxia, DNA damage, and cell invasion. Recently, through chronic exposure model, more extensive pathological effects due to areca nut have been found. These include the induction of autophagy, promotion of epithelial- mesenchymal transition, and facilitation of cancer stemness conversion. Clinical findings support these adverse effects. Oral submucosal fibrosis, a premalignant condition, is prevalent in the area with habitual chewing of areca nuts. Consistently, oral cancer patients with habitual chewing areca nut exhibit more aggressive phenotypes, including resistance to chemo-radiotherapy. In this review, we comprehensively discuss and concisely summarize the up-to-date molecular and cellular mechanisms by which areca nuts contribute to malignant transformation. This review may provide critical information regarding clinical applications in risk assessment, disease prevention, diagnosis, and personalized therapeutics for areca nut-induced oral malignancy.

Keywords: areca nut, oral cancer, oral submucosal fibrosis, reactive oxygen species, tissue hypoxia, cell invasion, epithelial-mesenchymal transition, cancer stemness