Cyclin D1 expression is induced by viral BARF1 and is overexpressed in EBV-associated gastric cancer.
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.
Wiech
Thorsten
T
Institute of Pathology, University Hospital Freiburg, Breisacherstr, 115A, 79106 Freiburg, Germany.
Nikolopoulos
Elisabeth
E
Lassman
Silke
S
Heidt
Timo
T
Schöpflin
Anja
A
Sarbia
Mario
M
Werner
Martin
M
Shimizu
Yuko
Y
Sakka
Emna
E
Ooka
Tadamasa
T
zur Hausen
Axel
A
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*
C086495:BARF1 protein, Human herpesvirus 4; D056741:Cyclin D; D016213:Cyclins; D014764:Viral Proteins