title: Cyclin D1 expression is induced by viral BARF1 and is overexpressed in EBV-associated gastric cancer.
abstract: Approximately 10% of gastric carcinomas (GC) worldwide are associated with Epstein-Barr virus (EBV). GC is one of the most frequent human malignancies associated with EBV. The latent expression of the EBV-oncogene BARF1 is restricted to epithelial malignancies. To investigate the underlying BARF1-related mechanisms of oncogenic epithelial transformation, we analyzed gene expression profiles of a BARF1-transfected epithelial (HaCaT+) and the corresponding BARF1-negative (HaCaT-) cell line by cDNA microarray analysis. Real-time PCR was performed to confirm the cDNA microarray results. In addition, immunohistochemistry and fluorescence in situ hybridization were performed on a tissue microarray of 181 GC including 11 EBV-associated GC. Among other genes cyclin D1 expression was significantly upregulated in HaCaT+ on the transcriptional and protein level. Cyclin D1 protein expression in GC revealed a significant overexpression of cyclin D1 in EBV-associated GC (p<0.012) but not in EBV-negative GC. Cyclin D1 FISH showed that cyclin D1 overexpression was not due to gene amplification in EBV-associated GC. Cyclin D1 is induced in HaCaT+ by BARF1 and is overexpressed in EBV-associated GC indicating an interaction of viral BARF1 and cyclin D1.
authors.affiliation: Institute of Pathology, University Hospital Freiburg, Breisacherstr, 115A, 79106 Freiburg, Germany.
authors.forename: Thorsten
authors.initials: T
authors.lastname: Wiech
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Nikolopoulos
authors.forename: Silke
authors.initials: S
authors.lastname: Lassman
authors.forename: Timo
authors.initials: T
authors.lastname: Heidt
authors.forename: Anja
authors.initials: A
authors.lastname: Schöpflin
authors.forename: Mario
authors.initials: M
authors.lastname: Sarbia
authors.forename: Martin
authors.initials: M
authors.lastname: Werner
authors.forename: Yuko
authors.initials: Y
authors.lastname: Shimizu
authors.forename: Emna
authors.initials: E
authors.lastname: Sakka
authors.forename: Tadamasa
authors.initials: T
authors.lastname: Ooka
authors.forename: Axel
authors.initials: A
authors.lastname: zur Hausen
mesh_terms: D002460:Cell Line; D056741:Cyclin D; D016213:Cyclins / Q000096:biosynthesis*; D020031:Epstein-Barr Virus Infections / Q000378:metabolism*; D020869:Gene Expression Profiling; D006801:Humans; D020411:Oligonucleotide Array Sequence Analysis; D013274:Stomach Neoplasms / Q000378:metabolism* / Q000821:virology*; D014162:Transfection; D015854:Up-Regulation; D014764:Viral Proteins / Q000502:physiology*
chemical_list: C086495:BARF1 protein, Human herpesvirus 4; D056741:Cyclin D; D016213:Cyclins; D014764:Viral Proteins