title: 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.
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.
authors.affiliation: Department of Medical Microbiology, School of Medicine, Wuhan University, Wuhan, China.
authors.forename: H
authors.initials: H
authors.lastname: Yu
authors.affiliation: State Key Laboratory of Proteomics, Department of Neurobiology, Beijing Institute of Basic Medical Sciences, Beijing, China.
authors.forename: T
authors.identifier: 0000000317016618
authors.initials: T
authors.lastname: Liu
authors.affiliation: Department of Urology, Zhongnan Hospital, Wuhan University, Wuhan, China.
authors.forename: Z
authors.initials: Z
authors.lastname: Zhao
authors.affiliation: Department of Medical Microbiology, School of Medicine, Wuhan University, Wuhan, China.
authors.forename: Y
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Department of Medical Microbiology, School of Medicine, Wuhan University, Wuhan, China.
authors.forename: J
authors.initials: J
authors.lastname: Zeng
authors.affiliation: State Key Laboratory of Proteomics, Department of Neurobiology, Beijing Institute of Basic Medical Sciences, Beijing, China.
authors.forename: S
authors.initials: S
authors.lastname: Liu
authors.affiliation: Department of Medical Microbiology, School of Medicine, Wuhan University, Wuhan, China.
authors.forename: F
authors.initials: F
authors.lastname: Zhu
mesh_terms: D000818:Animals; D001483:Base Sequence; D002295:Carcinoma, Transitional Cell / Q000235:genetics* / Q000378:metabolism / Q000821:virology; D049109:Cell Proliferation; D002897:Chromosomes, Human, Pair 7 / Q000235:genetics*; D004252:DNA Mutational Analysis; D020077:Endogenous Retroviruses / Q000235:genetics*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D015686:Gene Products, env / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008875:Middle Aged; D008969:Molecular Sequence Data; D009368:Neoplasm Transplantation; D017354:Point Mutation; D011257:Pregnancy Proteins / Q000235:genetics* / Q000378:metabolism; D011401:Promoter Regions, Genetic; D020598:Proto-Oncogene Proteins c-myb / Q000378:metabolism*; D051381:Rats; D020079:Terminal Repeat Sequences; D015854:Up-Regulation; D001749:Urinary Bladder Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000821:virology
chemical_list: D015686:Gene Products, env; D011257:Pregnancy Proteins; D020598:Proto-Oncogene Proteins c-myb; C405335:syncytin