Mutations in 3′-long terminal repeat of HERV-W family in chromosome 7 upregulate syncytin-1 expression in urothelial cell carcinoma of the bladder through interacting with c-Myb
Mutations in 3′-long terminal repeat of HERV-W family in chromosome 7 upregulate syncytin-1 expression in urothelial cell carcinoma of the bladder through interacting with c-Myb
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DOI：
10.1038/onc.2013.366
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发表时间：
2014-07
期刊：
影响因子：
8
通讯作者：
Honggang Yu;T. Liu;Z. Zhao;Yatang Chen;J. Zeng;Shujun Liu;F. Zhu
中科院分区：
文献类型：
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作者：
Honggang Yu;T. Liu;Z. Zhao;Yatang Chen;J. Zeng;Shujun Liu;F. Zhu
人类内源性逆转录病毒（HERV）占人类基因组的18%。最近的研究报道，多个HERV基因和长末端重复序列（LTR）参与人类肿瘤的发生。我们发现HERV-W env（syncytin-1）在75.6%（62/82）的膀胱尿路上皮细胞癌（UCC）组织中过表达，而在癌旁组织中仅为6.1%（5/82）（P< 0.001）。合胞素-1过表达增加永生化人尿路上皮细胞的增殖和活力。集落形成实验和体内肿瘤异种移植表明，合胞素-1过表达具有致癌潜力。87.8%（72/82）的UCC组织中存在Syncytin-13 ′-LTR突变（142 T> C和277 A> G）。UCC组织中3′-LTR正常表达率为12.2%（10/82），而癌旁组织中3′-LTR正常表达率为95.1%（78/82）（P< 0.001）。有趣的是，3′-LTR突变与syncytin-1过表达显著相关。荧光素酶分析和表达分析表明，3′-LTR突变，尤其是142 T> C突变，增强了syncytin-1启动子的活性和表达。计算机模拟分析、电泳迁移率改变分析和染色质免疫沉淀分析证实了突变发生时c-Myb与3′-LTR的结合。发现这种交替相互作用依赖于142 T> C突变。C-Myb通过与突变的3′-LTRs结合激活合胞素1启动子活性和表达。总之，这些数据表明合胞素-1过表达可能是UCC风险的指标。3′-LTR突变可能上调syncytin-1的表达，使其通过与c-Myb相互作用参与UCC的发生和发展。
Human endogenous retrovirus (HERV) accounts for∼ 8% of the human genome. Recent studies have reported that multiple HERV genes and long terminal repeats (LTRs) are involved in human tumorigenesis. Here we demonstrated that HERV-W env (syncytin-1) was overexpressed in 75.6%(62/82) of urothelial cell carcinoma (UCC) tissues of the bladder compared with only 6.1%(5/82) of matched tumor-adjacent tissues (P< 0.001). Syncytin-1 overexpression increased proliferation and viability of immortalized human uroepithelial cells. Colony-formation experiments and in-vivo tumor xenografts suggested that syncytin-1 overexpression had oncogenic potential. Syncytin-1 3′-LTR mutations (142T> C and 277A> G) were present in 87.8%(72/82) of UCC tissues. Normal 3′-LTR was found in 12.2%(10/82) of UCC tissues compared with 95.1%(78/82) of matched tumor-adjacent tissues (P< 0.001). Interestingly, 3′-LTR mutations were significantly associated with syncytin-1 overexpression. Luciferase assay and expression analysis revealed that 3′-LTR mutations, especially the 142T> C mutation, enhanced the syncytin-1 promoter activity and expression. In-silico analysis, electrophoretic mobility shift assays and chromatin immunoprecipitation assays demonstrated the binding of c-Myb to 3′-LTRs when the mutations occurred. This alternative interaction was found to be dependent on 142T> C mutation. C-Myb activated syncytin-1 promoter activity and expression by binding to mutant 3′-LTRs. Taken together, these data indicate that syncytin-1 overexpression may be an indicator of UCC risk. The 3′-LTR mutations may upregulate syncytin-1 expression, enabling it to participate in UCC tumorigenesis and development by interacting with c-Myb.