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Open Access Publications from the University of California

The mitochondrial chaperone Prohibitin 1 negatively regulates interleukin-8 in human liver cancers.

  • Author(s): Yang, Jin Won
  • Murray, Ben
  • Barbier-Torres, Lucia
  • Liu, Ting
  • Liu, Zhenqiu
  • Yang, Heping
  • Fan, Wei
  • Wang, Jiaohong
  • Li, Yuan
  • Seki, Ekihiro
  • Mato, José M
  • Lu, Shelly C
  • et al.

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Prohibitin 1 (PHB1) is a mitochondrial chaperone whose expression is dysregulated in cancers. In liver cancer, PHB1 acts as a tumor suppressor but the mechanisms of tumor suppression are incompletely understood. Here we aimed to determine PHB1 target genes to better understand how PHB1 influences liver tumorigenesis. Using RNA-seq analysis, we found interleukin-8 (IL-8) to be one of the most highly upregulated genes following PHB1 silencing in HepG2 cells. Induction of IL-8 expression also occurred in multiple liver and non-liver cancer cell lines. We examined samples from 178 patients with hepatocellular carcinoma (HCC) and found that IL-8 mRNA levels were increased, while PHB1 mRNA levels were decreased, in the tumors compared to adjacent non-tumorous tissues. Notably, HCC patients with high IL-8 expression have significantly reduced survival. An inverse correlation between PHB1 and IL-8 mRNA levels is found in HCCs with reduced PHB1 expression. To understand the molecular basis for these observations, we altered PHB1 levels in liver cancer cells. Overexpression of PHB1 resulted in lowered IL-8 expression and secretion. Silencing PHB1 increased JNK and NF-κB activity, induced nuclear accumulation of c-JUN and p65 and enhanced their binding to the IL-8 promoter containing AP-1 and NF-κB elements. Conditioned medium from PHB1-silenced HepG2 cells increased migration and invasion of parental HepG2 and SK-hep-1 cells, and this was blocked by co-treatment with neutralizing IL-8 antibody. In summary, our findings show that reduced PHB1 expression induces IL-8 transcription by activating NF-κB and AP-1, resulting in enhanced IL-8 expression and release to promote tumorigenesis.

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This item is under embargo until February 5, 2020.