title: The cytomegalovirus protein UL138 induces apoptosis of gastric cancer cells by binding to heat shock protein 70.
abstract: It has been hypothesized that human cytomegalovirus (HCMV) could act as a tumor promoter and play an "oncomodulatory" role in the neoplastic process of several human malignancies. However, we demonstrate for the first time that UL138, a HCMV latency-associated gene, could act as a tumor inhibitor in gastric cancer (GC). The expression of UL138 is down-regulated in HCMV positive gastric adenocarcinoma tissues, especially in poorly or none differentiated tumors. Overexpression of UL138 in several human GC cell lines inhibits cell viability and induces apoptosis, in association with the reduction of an anti-apoptotic Bcl-2 protein and the induction of cleaved caspase-3 and caspase-9. Moreover, protein array analysis reveals that UL138 interacts with a chaperone protein, heat shock protein 70 (HSP70). This interaction is confirmed by immunoprecipitation and immunostaining in situ in GC cell lines. In addition, this UL138-mediated cancer cell death could efficiently lead to suppression of human tumor growth in a xenograft animal model of GC. In conclusion, these results uncover a previously unknown role of the cytomegalovirus protein UL138 in inducing GC cells apoptosis, which might imply a general mechanism that viral proteins inhibit cancer growth in interactions with both chaperones and apoptosis-related proteins. Our findings might provide a potential target for new therapeutic strategies of GC treatment.
authors.affiliation: Department of General Surgery, First Affiliated Hospital, Wenzhou Medical University, Wenzhou, China.
authors.forename: Wenjing
authors.initials: W
authors.lastname: Chen
authors.affiliation: Experimental Center, Wenzhou Medical University, Wenzhou, China.
authors.forename: Kezhi
authors.initials: K
authors.lastname: Lin
authors.affiliation: Department of General Surgery, First Affiliated Hospital, Wenzhou Medical University, Wenzhou, China.
authors.forename: Liang
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Department of Microbiology and Immunology, Institute of Molecular Virology and Immunology, Institute of Tropical Medicine, Wenzhou Medical University, Wenzhou, China.
authors.forename: Gangqiang
authors.initials: G
authors.lastname: Guo
authors.affiliation: Department of General Surgery, First Affiliated Hospital, Wenzhou Medical University, Wenzhou, China.
authors.forename: Xiangwei
authors.initials: X
authors.lastname: Sun
authors.affiliation: Department of Rheumatology, First Affiliated Hospital, Wenzhou Medical University, Wenzhou, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Chen
authors.affiliation: Department of Microbiology and Immunology, Institute of Molecular Virology and Immunology, Institute of Tropical Medicine, Wenzhou Medical University, Wenzhou, China.
authors.forename: Lulu
authors.initials: L
authors.lastname: Ye
authors.affiliation: Department of Microbiology and Immunology, Institute of Molecular Virology and Immunology, Institute of Tropical Medicine, Wenzhou Medical University, Wenzhou, China.
authors.forename: Sisi
authors.initials: S
authors.lastname: Ye
authors.affiliation: Department of General Surgery, First Affiliated Hospital, Wenzhou Medical University, Wenzhou, China.
authors.forename: Chenchen
authors.initials: C
authors.lastname: Mao
authors.affiliation: Department of General Surgery, First Affiliated Hospital, Wenzhou Medical University, Wenzhou, China.
authors.forename: Jianfeng
authors.initials: J
authors.lastname: Xu
authors.affiliation: Department of Rheumatology, First Affiliated Hospital, Wenzhou Medical University, Wenzhou, China.
authors.forename: Lifang
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Department of Microbiology and Immunology, Institute of Molecular Virology and Immunology, Institute of Tropical Medicine, Wenzhou Medical University, Wenzhou, China.|Key Laboratory of Molecular Virology and Immunology, Unit of Pathogen-Host Interaction and Epigenetics, Institut Pasteur of Shanghai, Shanghai, China.
authors.forename: Lubin
authors.initials: L
authors.lastname: Jiang
authors.affiliation: Department of General Surgery, First Affiliated Hospital, Wenzhou Medical University, Wenzhou, China.
authors.forename: Xian
authors.initials: X
authors.lastname: Shen
authors.affiliation: Department of Microbiology and Immunology, Institute of Molecular Virology and Immunology, Institute of Tropical Medicine, Wenzhou Medical University, Wenzhou, China.
authors.forename: Xiangyang
authors.initials: X
authors.lastname: Xue
mesh_terms: D000818:Animals; D017209:Apoptosis; D015153:Blotting, Western; D049109:Cell Proliferation; D003587:Cytomegalovirus / Q000378:metabolism*; D005260:Female; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D018840:HSP70 Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007124:Immunoenzyme Techniques; D047468:Immunoprecipitation; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008875:Middle Aged; D011379:Prognosis; D040081:Protein Array Analysis; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013274:Stomach Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D014407:Tumor Cells, Cultured; D014764:Viral Proteins / Q000235:genetics / Q000378:metabolism*; D023041:Xenograft Model Antitumor Assays
chemical_list: D018840:HSP70 Heat-Shock Proteins; D012333:RNA, Messenger; D014764:Viral Proteins
keywords: HSP70; UL138; apoptosis; cytomegalovirus; gastric cancer