title: Longer warm ischemia can accelerate tumor growth through the induction of HIF-1α and the IL-6-JAK-STAT3 signaling pathway in a rat hepatocellular carcinoma model.
abstract: BACKGROUND
  The present study aimed to investigate the impact of the duration of hepatic pedicle clamping (HPC) on tumor growth after major hepatectomy in a rat model.
  
  
  METHODS
  Rats were divided into four groups according to the length of HPC during 70% partial hepatectomy followed by N1S1 tumor cell implantation: group 1, without HPC; group 2, with 5-min HPC; group 3, 10-min HPC; and group 4, 15-min HPC. At three weeks after tumor cell implantation, liver tumor growth and its possible mechanisms were investigated.
  
  
  RESULTS
  The number and largest diameter of liver tumor were significantly greater in group 4. At 6 h after reperfusion, serum levels of inflammatory cytokines including interleukin (IL)-6 were significantly higher in group 4 compared with the other groups. In the tumor tissues, the expression of hypoxia inducible factor (HIF)-1α (P < 0.001 versus group 2, P < 0.001 versus group 3) and that of phospho-signal transducer and activator of transcription 3 (STAT3) (P < 0.001 versus group 2, P = 0.026 versus group 3) were significantly upregulated in group 4.
  
  
  CONCLUSIONS
  Longer HPC followed by reperfusion accelerated hepatocellular carcinoma growth through the induction of HIF-1α and the activation of the IL-6-JAK-STAT3 signaling pathway.
authors.affiliation: Division of Hepato-Biliary-Pancreatic Surgery and Transplantation, Department of Surgery, Graduate School of Medicine, Kyoto University, 54 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto, 606-8507, Japan.
authors.forename: Yuhei
authors.initials: Y
authors.lastname: Hamaguchi
authors.affiliation: Division of Hepato-Biliary-Pancreatic Surgery and Transplantation, Department of Surgery, Graduate School of Medicine, Kyoto University, 54 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto, 606-8507, Japan.
authors.forename: Akira
authors.initials: A
authors.lastname: Mori
authors.affiliation: Division of Hepato-Biliary-Pancreatic Surgery and Transplantation, Department of Surgery, Graduate School of Medicine, Kyoto University, 54 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto, 606-8507, Japan.
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Fujimoto
authors.affiliation: Division of Hepato-Biliary-Pancreatic Surgery and Transplantation, Department of Surgery, Graduate School of Medicine, Kyoto University, 54 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto, 606-8507, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Ito
authors.affiliation: Division of Hepato-Biliary-Pancreatic Surgery and Transplantation, Department of Surgery, Graduate School of Medicine, Kyoto University, 54 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto, 606-8507, Japan.
authors.forename: Taku
authors.initials: T
authors.lastname: Iida
authors.affiliation: Division of Hepato-Biliary-Pancreatic Surgery and Transplantation, Department of Surgery, Graduate School of Medicine, Kyoto University, 54 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto, 606-8507, Japan.
authors.forename: Shintaro
authors.initials: S
authors.lastname: Yagi
authors.affiliation: Division of Hepato-Biliary-Pancreatic Surgery and Transplantation, Department of Surgery, Graduate School of Medicine, Kyoto University, 54 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto, 606-8507, Japan.
authors.forename: Hideaki
authors.initials: H
authors.lastname: Okajima
authors.affiliation: Division of Hepato-Biliary-Pancreatic Surgery and Transplantation, Department of Surgery, Graduate School of Medicine, Kyoto University, 54 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto, 606-8507, Japan.
authors.forename: Toshimi
authors.initials: T
authors.lastname: Kaido
authors.affiliation: Division of Hepato-Biliary-Pancreatic Surgery and Transplantation, Department of Surgery, Graduate School of Medicine, Kyoto University, 54 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto, 606-8507, Japan.
authors.forename: Shinji
authors.initials: S
authors.lastname: Uemoto
mesh_terms: D000818:Animals; D014408:Biomarkers, Tumor / Q000378:metabolism*; D001707:Biopsy, Needle; D015153:Blotting, Western; D006528:Carcinoma, Hepatocellular / Q000473:pathology / Q000601:surgery*; D006498:Hepatectomy / Q000009:adverse effects* / Q000379:methods; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D007150:Immunohistochemistry; D015850:Interleukin-6 / Q000378:metabolism; D008113:Liver Neoplasms / Q000473:pathology / Q000601:surgery*; D008297:Male; D009364:Neoplasm Recurrence, Local / Q000453:epidemiology / Q000473:pathology*; D009374:Neoplasms, Experimental; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D050796:STAT3 Transcription Factor / Q000378:metabolism; D012680:Sensitivity and Specificity; D015398:Signal Transduction; D015996:Survival Rate; D047368:Tumor Burden; D052096:Warm Ischemia / Q000009:adverse effects*
chemical_list: D014408:Biomarkers, Tumor; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; C508600:IL6 protein, human; D015850:Interleukin-6; D050796:STAT3 Transcription Factor
keywords: Hepatic ischemia-reperfusion injury; Hepatocellular carcinoma; Hypoxia inducible factor-1α; Interleukin-6; Janus kinases and signal transducer and activator of transcription 3 pathway