B Cell-Specific Moloney Murine Leukemia Virus Integration Site 1 (Bmi-1, Bmi1), an epigenetic protein, is necessary for normal stem cell self-renewal in adult animals and for cancer stem cell (CSC) functions in adult animals. To elucidate the functions of Bmi-1 in the oral cavity we created a transgenic mouse line (KrTBmi-1) that expresses ectopic, Flag-tagged Bmi-1 in tongue basal epithelial stem cells only upon doxycycline (DOX) treatment. Genome wide transcriptomics and Ingenuity Pathway Analysis identified several pathways altered by exogenous Bmi-1 expression in the normal tongue epithelium, including EIF2 signaling (P value = 1.58 x 10-49), mTOR signaling (P value = 2.45 x 10-12), oxidative phosphorylation (P = 6.61 x 10-3) and glutathione redox reactions I (P = 1.74 x 10-2). Overall, our data indicate that ectopic Bmi-1 expression has an impact on normal tongue epithelial homeostasis. We then assessed the KrTBmi-1 mice in the 4-nitroquinoline 1-oxide (4-NQO) model of oral carcinogenesis. We found that 80% of mice expressing exogenous Bmi-1 (+DOX, +4-NQO KrTBmi-1; N = 10) developed tumors classified as grade 3 or higher, compared to 60% and 40% of mice expressing just endogenous Bmi-1 (+DOX, +4-NQO Kr and -DOX, +4-NQO KrTBmi-1 groups, respectively; N = 10/group; P value = <0.0001); and 30% of mice expressing ectopic Bmi-1 mice developed 20 or more lesions compared to 10% of mice expressing only endogenous Bmi-1 (P = .009). This demonstrates that exogenous Bmi-1 expression increases the susceptibility of mice to 4-NQO-induced oral carcinogenesis, strengthening the evidence for Bmi-1 as a therapeutic target in human oral squamous cell carcinoma.

中文翻译：

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强力霉素诱导的外源性Bmi-1表达增强了口腔鳞状细胞癌小鼠模型中的肿瘤形成。

B细胞特异性莫洛尼鼠白血病病毒整合位点1（Bmi-1，Bmi1）是一种表观遗传蛋白，对于成年动物正常的干细胞自我更新和成年动物的癌症干细胞（CSC）功能是必需的。为了阐明Bmi-1在口腔中的功能，我们创建了一个转基因小鼠品系（KrTBmi-1），该品系仅在强力霉素（DOX）处理后才在舌基上皮干细胞中表达异位的，带有Flag标签的Bmi-1。全基因组转录组学和独创性途径分析确定了正常舌头上皮中外源性Bmi-1表达改变的几种途径，包括EIF2信号（P值= 1.58 x 10-49），mTOR信号（P值= 2.45 x 10-12），氧化磷酸化（P = 6.61 x 10-3）和谷胱甘肽氧化还原反应I（P = 1.74 x 10-2）。总体，我们的数据表明异位Bmi-1表达对正常舌头上皮稳态有影响。然后，我们在口腔致癌的4-硝基喹啉1-氧化物（4-NQO）模型中评估了KrTBmi-1小鼠。我们发现，表达外源Bmi-1（+ DOX，+ 4-NQO KrTBmi-1; N = 10）的小鼠中有80％的肿瘤被分类为3级或更高级别，而仅表达内源性Bmi的小鼠中有60％和40％ -1（+ DOX，+ 4-NQO Kr和-DOX，+ 4-NQO KrTBmi-1组; N = 10 /组; P值<0.0001）; 与表达仅内源性Bmi-1的小鼠中有10％的小鼠相比，表达异位Bmi-1的小鼠中有30％的小鼠出现了20个或更多的病变（P = .009）。这表明外源性Bmi-1表达增加了小鼠对4-NQO诱导的口腔致癌作用的敏感性，