title: Suppression of signal transducers and activators of transcription 1 in hepatocellular carcinoma is associated with tumor progression.
abstract: 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.
authors.affiliation: Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka, Japan.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Hosui
authors.forename: Peter
authors.initials: P
authors.lastname: Klover
authors.forename: Tomohide
authors.initials: T
authors.lastname: Tatsumi
authors.forename: Akio
authors.initials: A
authors.lastname: Uemura
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Nagano
authors.forename: Yuichiro
authors.initials: Y
authors.lastname: Doki
authors.forename: Masaki
authors.initials: M
authors.lastname: Mori
authors.forename: Naoki
authors.initials: N
authors.lastname: Hiramatsu
authors.forename: Tatsuya
authors.initials: T
authors.lastname: Kanto
authors.forename: Lothar
authors.initials: L
authors.lastname: Hennighausen
authors.forename: Norio
authors.initials: N
authors.lastname: Hayashi
authors.forename: Tetsuo
authors.initials: T
authors.lastname: Takehara
mesh_terms: D000368:Aged; D000818:Animals; D001483:Base Sequence; D006528:Carcinoma, Hepatocellular / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D047369:Chromatin Immunoprecipitation; D017931:DNA Primers; D018450:Disease Progression; D005260:Female; D006801:Humans; D008113:Liver Neoplasms / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008875:Middle Aged; D050794:STAT1 Transcription Factor / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D017931:DNA Primers; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human