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.

Keywords: Hepatic ischemia-reperfusion injury; Hepatocellular carcinoma; Hypoxia inducible factor-1α; Interleukin-6; Janus kinases and signal transducer and activator of transcription 3 pathway.