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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

Oncogene volume 33, pages 3947–3958 (2014)Cite this article

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Abstract

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.

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Acknowledgements

We thank Wei Jin (Fudan University, Shanghai, China) for providing the plasmid pCMV-c-Myb. We would like to thank Don Banting, Awadhesh Kumar Sah and Navin Shrestha for polishing our writing. This work was supported by grants from the National Natural Sciences Foundation of China (No. 81271820, No. 30870789 and No. 30300117), the Stanley Foundation from the Stanley Medical Research Institute (SMRI), USA (No. 06R-1366) for Dr F Zhu, Hubei Provincial Natural Science Foundation for Innovative Research Team (No. 2012FFA043) and the project of Innovative Research Team of Wuhan University (No. 274041).

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  1. H Yu and T Liu: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Medical Microbiology, School of Medicine, Wuhan University, Wuhan, China

    H Yu, Y Chen, J Zeng & F Zhu

  2. Department of Neurobiology, State Key Laboratory of Proteomics, Beijing Institute of Basic Medical Sciences, Beijing, China

    T Liu & S Liu

  3. Department of Urology, Zhongnan Hospital, Wuhan University, Wuhan, China

    Z Zhao

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Yu, H., Liu, T., Zhao, Z. et al. 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. Oncogene 33, 3947–3958 (2014). https://doi.org/10.1038/onc.2013.366

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