Chang Pei-Ying, Kuo Tzer-Min, Chen Po-Ku, Lin You-Zhe, Hua Chun-Hung, Chen Yuan-Chien, Ko Ying-Chin
Graduate Institute of Clinical Medical Science, China Medical University , Taichung, Taiwan.
Department of Oral and Maxillofacial Surgery, China Medical University Hospital , Taichung, Taiwan.
J Agric Food Chem. 2017 Nov 29;65(47):10197-10205. doi: 10.1021/acs.jafc.7b03999. Epub 2017 Nov 16.
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.
槟榔与口腔鳞状细胞癌（OSCC）的发生密切相关。槟榔碱的代谢产物氧化槟榔碱（ANO）在NOD/SCID小鼠中表现出口腔纤维化作用。半胱天冬酶-8（Caspase-8）是由CASP8基因编码的一种半胱氨酸蛋白酶，是通过死亡受体介导的外源性凋亡途径的核心介质。已有报道称OSCC中Caspase-8失调。本研究调查了Caspase-8在ANO诱导的口腔鳞状上皮增生中的调节作用，该增生代表口腔癌发生的初始高增殖阶段。通过OSCC样本的全外显子测序鉴定出CASP8体细胞突变。免疫组织化学染色显示，在ANO诱导的NOD-SCID和C57BL/6小鼠增生中，Caspase-8表达上调。在ANO处理的DOK细胞中，CASP8、凋亡蛋白酶激活因子-1（APAF-1）、促凋亡蛋白BAX和BAD的表达水平升高。在ANO诱导的增生性病变中检测到Caspase-8水平升高与增殖细胞核抗原（PCNA）水平的共定位，而在γ-H2A.X、Caspase-3和上调的Caspase-8之间未观察到共定位。这些发现表明，在ANO介导的口腔肿瘤发生的初始阶段，Caspase-8的上调参与细胞增殖而非凋亡。
