Suppression of signal transducers and activators of transcription 1 in hepatocellular carcinoma is associated with tumor progression

Atsushi Hosui, Peter Klover, Tomohide Tatsumi, Akio Uemura, Hiroaki Nagano, Yuichiro Doki, Masaki Mori, Naoki Hiramatsu, Tatsuya Kanto, Lothar Hennighausen, Norio Hayashi, Tetsuo Takehara

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14 Citations (Scopus)


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.

Original languageEnglish
Pages (from-to)2774-2784
Number of pages11
JournalInternational Journal of Cancer
Issue number12
Publication statusPublished - Dec 15 2012
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research


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