Premium
Arecoline N‐oxide regulates oral squamous cell carcinoma development through NOTCH1 and FAT1 expressions
Author(s) -
Kuo TzerMin,
Nithiyanantham Srinivasan,
Lee ChiPin,
Hsu HuiTing,
Luo ShunYuan,
Lin YouZhe,
Yeh KunTu,
Ko YingChin
Publication year - 2019
Publication title -
journal of cellular physiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.529
H-Index - 174
eISSN - 1097-4652
pISSN - 0021-9541
DOI - 10.1002/jcp.28084
Subject(s) - arecoline , areca , downregulation and upregulation , cancer research , carcinogen , carcinogenesis , betel , cancer , immunohistochemistry , gene knockdown , hyperplasia , metabolite , chemistry , medicine , biology , biochemistry , apoptosis , receptor , muscarinic acetylcholine receptor , structural engineering , nut , engineering , gene
Abstract Areca nut has been evaluated as a group I carcinogen to humans. However, the exact compounds of areca nut causing oral cancer remain unproven. Previous findings from our lab revealed that arecoline N‐oxide (ANO), a metabolite of arecoline, exhibits an oral fibrotic effect in immune‐deficient NOD/SCID mice. The aim of this study is to investigate the oral potentially malignant disorders (OPMD) inductive activity between areca‐alkaloid arecoline and its metabolite ANO in C57BL/6 mice. Our findings show that ANO showed higher activity in inducing hyperplasia with leukoplakia and collagen deposition in C57BL/6 mice compared with the arecoline treated groups. Importantly, immunohistochemical studies showed significant upregulation of NOTCH1, HES1, FAT1, PCNA, and Ki67 expressions in the pathological hyperplastic part. In addition, in vitro studies showed that upregulation of NOTCH1 and FAT1 expressions in ANO treated HGF‐1 and DOK cell models. We found that NOTCH1 regulates TP53 expression from NOTCH1 knockdown oral cancer cells. The DNA damage was significantly increased after arecoline and ANO treatment. Further, we found that arecoline‐induced H2AX expression was regulated by FMO3. Altogether, our findings show that ANO exhibited higher toxicity in OPMD activity and play a significant role in the induction of areca nut mediated oral tumorigenesis.