Signal transducers and activators of transcription (STAT) 1 plays a pivotal role in cell-cycle and cell-fate determination, and
vascular endothelial growth factor (
VEGF) also contributes
tumor growth. Recently,
interferon (IFN) α has been reported to be effective for prevention of
hepatocellular carcinomas (HCCs) recurrence, but the detailed mechanisms remain elusive. In vitro,
cobalt chloride-treated
VEGF induction and
hypoxia responsive
element (HRE) promoter activity were inhibited by IFNs and this abrogation was cancelled by introduction of
small interfering RNA for STAT1. Immunoprecipitation/
chromatin immunoprecipitation analyses showed STAT1 bound to
hypoxia-inducible factor (HIF)-1α and dissociated HIF-complex from HRE promoter lesion. In a xenograft model using Balb/c nude mice,
tumor growth was suppressed by IFNα through inhibition of
VEGF expression and it was oppositely enhanced when STAT1-deleted cells were injected. This augmentation was due to upregulation of
VEGF and
hyaluronan synthase 2. In human samples, 29 HCCs were resected, divided into two groups based on STAT1 activation in
tumor and the clinical features were investigated. Patients with suppressed STAT1 activity had a shorter recurrence-free survival. Histological and
reverse transcriptase-polymerase chain reaction (RT-PCR) analyses showed portal vein microinvasion and increased
VEGF levels in
tumors from suppressed STAT1 group. These human samples also showed a reverse correlation between
VEGF and STAT1-regulated genes expression. These results in vitro and in vivo suggested that IFNα are potential candidates for prevention of vessel invasion acting through inhibition of
VEGF expression and need to be properly used when STAT1 expression is suppressed.