Abstract：
Cyclin D1 is frequently overexpressed in esophageal squamous cell carcinoma (ESCC) and is considered a key driver of this disease. Mutations in FBXO4, F-box specificity factor that directs SCF-mediated ubiquitylation of cyclin D1, occur in ESCC with concurrent overexpression of cyclin D1 suggesting a potential tumor suppressor role for FBXO4. To evaluate the contribution of FBXO4-dependent regulation cyclin D1 in esophageal squamous cell homeostasis, we exposed FBXO4 knockout mice to N-nitrosomethylbenzylamine (NMBA), an esophageal carcinogen. Our results revealed that loss of FBXO4 function facilitates NMBA induced papillomas in FBXO4 het (+/-) and null (-/-) mice both by numbers and sizes 11 months after single dose NMBA treatment at 2mg/kg by gavage when compared to that in wt (+/+) mice (P < 0.01). No significant difference was noted between heterozygous or nullizygous mice consistent with previous work. To assess cyclin D1/CDK4 dependence, mice were treated with the CDK4/6 specific inhibitor, PD0332991, for 4 weeks. PD0332991 treatment (150mg/kg daily), reduced tumor size and tumor number. Collectively, our data support a role for FBXO4 as a suppressor of esophageal tumorigenesis.
摘要：
细胞周期蛋白D1在食管鳞状细胞癌（ESCC）中经常过表达，被认为是该疾病的关键驱动因素。FBXO4中的突变，即指导SCF介导的细胞周期蛋白D1泛素化的F-box特异性因子，在ESCC中同时发生细胞周期蛋白D1的过表达，表明FBXO4具有潜在的肿瘤抑制作用。为了评估FBXO4依赖性调节细胞周期蛋白D1在食管鳞状细胞稳态中的作用，我们将FBXO4敲除小鼠暴露于N-亚硝基甲基苄胺（NMBA），食道致癌物.我们的结果表明，FBXO4功能的丧失促进了FBXO4het（/-）和null（-/-）小鼠中NMBA诱导的乳头状瘤的数量和大小，在单次剂量NMBA治疗后11个月通过管饲法以2mg/kg与wt（/）小鼠相比（P<0.01）。与先前的工作一致,在杂合或无效小鼠之间没有注意到显著差异。为了评估细胞周期蛋白D1/CDK4依赖性，用CDK4/6特异性抑制剂治疗小鼠，PD0332991，持续4周。PD0332991治疗（每天150mg/kg），减少肿瘤大小和肿瘤数量。总的来说，我们的数据支持FBXO4作为食管肿瘤发生的抑制因子的作用.
