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

Research output: Contribution to journalArticle

7 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)2774-2784
Number of pages11
JournalInternational Journal of Cancer
Volume131
Issue number12
DOIs
Publication statusPublished - Dec 15 2012
Externally publishedYes

Fingerprint

STAT1 Transcription Factor
Vascular Endothelial Growth Factor A
Hepatocellular Carcinoma
Neoplasms
Interferons
Hypoxia-Inducible Factor 1
Recurrence
Chromatin Immunoprecipitation
Growth
Portal Vein
Reverse Transcriptase Polymerase Chain Reaction
Immunoprecipitation
Heterografts
Nude Mice
Small Interfering RNA
Cell Cycle
Up-Regulation
Gene Expression
Survival

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

Cite this

Suppression of signal transducers and activators of transcription 1 in hepatocellular carcinoma is associated with tumor progression. / Hosui, Atsushi; Klover, Peter; Tatsumi, Tomohide; Uemura, Akio; Nagano, Hiroaki; Doki, Yuichiro; Mori, Masaki; Hiramatsu, Naoki; Kanto, Tatsuya; Hennighausen, Lothar; Hayashi, Norio; Takehara, Tetsuo.

In: International Journal of Cancer, Vol. 131, No. 12, 15.12.2012, p. 2774-2784.

Research output: Contribution to journalArticle

Hosui, A, Klover, P, Tatsumi, T, Uemura, A, Nagano, H, Doki, Y, Mori, M, Hiramatsu, N, Kanto, T, Hennighausen, L, Hayashi, N & Takehara, T 2012, 'Suppression of signal transducers and activators of transcription 1 in hepatocellular carcinoma is associated with tumor progression', International Journal of Cancer, vol. 131, no. 12, pp. 2774-2784. https://doi.org/10.1002/ijc.27580
Hosui, Atsushi ; Klover, Peter ; Tatsumi, Tomohide ; Uemura, Akio ; Nagano, Hiroaki ; Doki, Yuichiro ; Mori, Masaki ; Hiramatsu, Naoki ; Kanto, Tatsuya ; Hennighausen, Lothar ; Hayashi, Norio ; Takehara, Tetsuo. / Suppression of signal transducers and activators of transcription 1 in hepatocellular carcinoma is associated with tumor progression. In: International Journal of Cancer. 2012 ; Vol. 131, No. 12. pp. 2774-2784.
@article{1ca66fb9b17645ceb4a985fcd1cfc7cd,
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.",
author = "Atsushi Hosui and Peter Klover and Tomohide Tatsumi and Akio Uemura and Hiroaki Nagano and Yuichiro Doki and Masaki Mori and Naoki Hiramatsu and Tatsuya Kanto and Lothar Hennighausen and Norio Hayashi and Tetsuo Takehara",
year = "2012",
month = "12",
day = "15",
doi = "10.1002/ijc.27580",
language = "English",
volume = "131",
pages = "2774--2784",
journal = "International Journal of Cancer",
issn = "0020-7136",
publisher = "Wiley-Liss Inc.",
number = "12",

}

TY - JOUR

T1 - Suppression of signal transducers and activators of transcription 1 in hepatocellular carcinoma is associated with tumor progression

AU - Hosui, Atsushi

AU - Klover, Peter

AU - Tatsumi, Tomohide

AU - Uemura, Akio

AU - Nagano, Hiroaki

AU - Doki, Yuichiro

AU - Mori, Masaki

AU - Hiramatsu, Naoki

AU - Kanto, Tatsuya

AU - Hennighausen, Lothar

AU - Hayashi, Norio

AU - Takehara, Tetsuo

PY - 2012/12/15

Y1 - 2012/12/15

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=84867858861&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84867858861&partnerID=8YFLogxK

U2 - 10.1002/ijc.27580

DO - 10.1002/ijc.27580

M3 - Article

C2 - 22488367

AN - SCOPUS:84867858861

VL - 131

SP - 2774

EP - 2784

JO - International Journal of Cancer

JF - International Journal of Cancer

SN - 0020-7136

IS - 12

ER -