Jack Birch Unit for Molecular Carcinogenesis, Department of Biology and York Biomedical Research Institute, University of York, Heslington, York, YO10 5DD, UK.
Faculty of Biological Sciences, School of Molecular and Cellular Pathology, University of Leeds, Leeds, UK.
Oncogene. 2022 Apr;41(15):2139-2151. doi: 10.1038/s41388-022-02235-8. Epub 2022 Feb 22.
Limited understanding of bladder cancer aetiopathology hampers progress in reducing incidence. Mutational signatures show the anti-viral apolipoprotein B mRNA editing enzyme catalytic polypeptide (APOBEC) enzymes are responsible for the preponderance of mutations in bladder tumour genomes, but no causative viral agent has been identified. BK polyomavirus (BKPyV) is a common childhood infection that remains latent in the adult kidney, where reactivation leads to viruria. This study provides missing mechanistic evidence linking reactivated BKPyV-infection to bladder cancer risk. We used a mitotically-quiescent, functionally-differentiated model of normal human urothelium to examine BKPyV-infection. BKPyV-infection led to significantly elevated APOBEC3A and APOBEC3B protein, increased deaminase activity and greater numbers of apurinic/apyrimidinic sites in the host urothelial genome. BKPyV Large T antigen (LT-Ag) stimulated re-entry from G0 into the cell cycle through inhibition of retinoblastoma protein and activation of EZH2, E2F1 and FOXM1, with cells arresting in G2. The single-stranded DNA displacement loops formed in urothelial cells during BKPyV-infection interacted with LT-Ag to provide a substrate for APOBEC3-activity. Addition of interferon gamma (IFNγ) to infected urothelium suppressed expression of the viral genome. These results support reactivated BKPyV infections in adults as a risk factor for bladder cancer in immune-insufficient populations.
对膀胱癌病因病理的认识有限，阻碍了发病率降低的研究进展。突变特征表明，抗病毒载脂蛋白 B mRNA 编辑酶催化多肽（APOBEC）酶负责膀胱肿瘤基因组中绝大多数突变的发生，但尚未确定致病病毒。BK 多瘤病毒（BKPyV）是一种常见的儿童感染病毒，在成人肾脏中潜伏，在那里重新激活会导致病毒尿。本研究提供了缺失的机制证据，将重新激活的 BKPyV 感染与膀胱癌风险联系起来。我们使用有丝分裂静止、功能分化的正常人类尿路上皮模型来研究 BKPyV 感染。BKPyV 感染导致 APOBEC3A 和 APOBEC3B 蛋白显著升高，脱氨酶活性增加，宿主尿路上皮基因组中的无嘌呤/无嘧啶位点增加。BKPyV 大 T 抗原（LT-Ag）通过抑制视网膜母细胞瘤蛋白和激活 EZH2、E2F1 和 FOXM1，使细胞在 G2 期停滞，从而刺激细胞从 G0 重新进入细胞周期。在 BKPyV 感染期间形成的尿路上皮细胞中的单链 DNA 置换环与 LT-Ag 相互作用，为 APOBEC3 活性提供了底物。在受感染的尿路上皮中添加干扰素 γ（IFNγ）可抑制病毒基因组的表达。这些结果支持成人重新激活的 BKPyV 感染是免疫功能不全人群膀胱癌的危险因素。
