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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.