Induction of APOBEC3-mediated genomic damage in urothelium implicates BK polyomavirus (BKPyV) as a hit-and-run driver for bladder cancer.
Induction of APOBEC3-mediated genomic damage in urothelium implicates BK polyomavirus (BKPyV) as a hit-and-run driver for bladder cancer.
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DOI：
10.1038/s41388-022-02235-8
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发表时间：
2022-04
期刊：
影响因子：
8
通讯作者：
Southgate J
中科院分区：
文献类型：
--
作者：
Baker SC;Mason AS;Slip RG;Skinner KT;Macdonald A;Masood O;Harris RS;Fenton TR;Periyasamy M;Ali S;Southgate J
对膀胱癌病因病理学的有限了解阻碍了降低发病率的进展。突变特征显示，抗病毒载脂蛋白B mRNA编辑酶催化多肽（APOBEC）酶是膀胱肿瘤基因组中突变占优势的原因，但尚未鉴定出致病病毒。BK多瘤病毒（BKPyV）是一种常见的儿童感染，在成人肾脏中保持潜伏，其中再活化导致病毒尿。这项研究提供了缺失的将重新激活的BKPyV感染与膀胱癌风险联系起来的机制证据。我们使用了一个有丝分裂静止，功能分化的正常人尿路上皮细胞模型来检查BKPyV感染。BKPyV感染导致APOBEC 3A和APOBEC 3B蛋白显著升高，脱氨酶活性增加，宿主尿路上皮基因组中脱嘌呤/脱嘧啶位点数量增加。BKPyV大T抗原（LT-Ag）通过抑制视网膜母细胞瘤蛋白和激活EZH 2、E2 F1和FOXM 1刺激从G 0重新进入细胞周期，细胞停滞在G2期。在BKPyV感染过程中在尿路上皮细胞中形成的单链DNA置换环与LT-Ag相互作用，为APOBEC 3活性提供底物。向感染的尿路上皮细胞中加入干扰素γ（IFNγ）可抑制病毒基因组的表达。这些结果支持成人中BKPyV再活化感染是免疫不足人群中膀胱癌的风险因素。
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.
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影响因子：
8.8
作者：
Fulciniti, Mariateresa;Lin, Charles Y.;Munshi, Nikhil C.
通讯作者：
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影响因子：
30.8
作者：
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