Autocrine growth of Epstein-Barr virus-positive gastric carcinoma cells mediated by an Epstein-Barr virus-encoded small RNA.
Although 5-10% of gastric carcinoma (GC) cases worldwide are associated with EBV, a human herpesvirus, it is still not clear what the precise contribution of the virus is to the pathogenesis of EBV-positive GC. Here we report that EBV infection induces expression of insulin-like growth factor 1 (IGF-I) in the GC-derived EBV-negative cell line NU-GC-3 and that the secreted IGF-I acts as an autocrine growth factor. Transfection of individual EBV latent genes into NU-GC-3 cells revealed that the EBV-encoded small RNA (EBER) was responsible for IGF-I expression. Addition of recombinant IGF-I accelerated growth of NU-GC-3 cells, whereas growth of the EBV-converted NU-GC-3 cells was blocked by treatment with an anti-IGF-I antibody. These results suggest that IGF-I induced by EBER acts as an autocrine growth factor for EBV-positive GC. These findings seem to be operative in vivo, as EBV-positive GC biopsies consistently express IGF-I, whereas EBV-negative GC biopsies do not. EBER is invariably expressed in EBV-associated malignancies including GC. The present findings strongly suggest that EBV directly affects the pathogenesis of EBV-positive GC and underline the importance of RNA molecules on cell growth regulation.
Iwakiri
Dai
D
Department of Tumor Virology, Institute for Genetic Medicine, Hokkaido University, N15 W7, Kita-ku, Sapporo 060-0815, Japan.
Eizuru
Yoshito
Y
Tokunaga
Masayoshi
M
Takada
Kenzo
K
D002455:Cell Division / Q000235:genetics; D045744:Cell Line, Tumor; D020031:Epstein-Barr Virus Infections / Q000378:metabolism / Q000821:virology; D004854:Herpesvirus 4, Human / Q000235:genetics*; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D012367:RNA, Viral / Q000096:biosynthesis / Q000235:genetics* / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013274:Stomach Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology* / Q000821:virology*; D015533:Transcriptional Activation; D014162:Transfection
D012367:RNA, Viral; D007334:Insulin-Like Growth Factor I