Jump to Main Content
Arecoline N-Oxide Upregulates Caspase-8 Expression in Oral Hyperplastic Lesions of Mice
- Chang, Pei-Ying, Kuo, Tzer-Min, Chen, Po-Ku, Lin, You-Zhe, Hua, Chun-Hung, Chen, Yuan-Chien, Ko, Ying-Chin
- Journal of agricultural and food chemistry 2017 v.65 no.47 pp. 10197-10205
- Areca, apoptosis, arecoline, betel nut, carcinogenesis, caspase-3, caspase-8, cell proliferation, death domain receptors, epithelium, genes, hyperplasia, immunohistochemistry, metabolites, mice, proliferating cell nuclear antigen, severe combined immunodeficiency, somatic mutation, squamous cell carcinoma, staining
- Areca nut is strongly associated with oral squamous cell carcinoma (OSCC) occurrence. Arecoline N-oxide (ANO), a metabolite of the areca alkaloid arecoline, exhibits an oral fibrotic effect in NOD/SCID mice. Caspase-8, a cysteine protease encoded by the CASP8 gene, is a central mediator in the extrinsic apoptotic pathway via death receptors. Deregulation of caspase-8 in OSCC has been reported. This study investigates the regulation of caspase-8 in ANO-induced oral squamous epithelial hyperplasia that represents the initial highly proliferative stage of oral carcinogenesis. CASP8 somatic mutations were identified from whole-exome sequencing of OSCC samples. Immunohistochemical staining showed upregulation of caspase-8 in ANO-induced hyperplasia of both NOD-SCID and C57BL/6 mice. Levels of expression of CASP8, APAF-1, BAX, and BAD increased in ANO-treated DOK cells. Co-localization of increased caspase-8 and PCNA levels was detected in ANO-induced hyperplastic lesions, whereas no co-localization among γ-H2A.X, caspase-3, and upregulated caspase-8 was observed. The findings indicate that upregulation of caspase-8 is involved in cell proliferation rather than apoptosis during the initial stage of ANO-mediated oral tumorigenesis.