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Inflammation mobilizes copper metabolism to promote colon tumorigenesis via an IL-17-STEAP4-XIAP axis.

  • Author(s): Liao, Yun;
  • Zhao, Junjie;
  • Bulek, Katarzyna;
  • Tang, Fangqiang;
  • Chen, Xing;
  • Cai, Gang;
  • Jia, Shang;
  • Fox, Paul L;
  • Huang, Emina;
  • Pizarro, Theresa T;
  • Kalady, Matthew F;
  • Jackson, Mark W;
  • Bao, Shideng;
  • Sen, Ganes C;
  • Stark, George R;
  • Chang, Christopher J;
  • Li, Xiaoxia
  • et al.
Abstract

Copper levels are known to be elevated in inflamed and malignant tissues. But the mechanism underlying this selective enrichment has been elusive. In this study, we report a axis by which inflammatory cytokines, such as IL-17, drive cellular copper uptake via the induction of a metalloreductase, STEAP4. IL-17-induced elevated intracellular copper level leads to the activation of an E3-ligase, XIAP, which potentiates IL-17-induced NFκB activation and suppresses the caspase 3 activity. Importantly, this IL-17-induced STEAP4-dependent cellular copper uptake is critical for colon tumor formation in a murine model of colitis-associated tumorigenesis and STEAP4 expression correlates with IL-17 level and XIAP activation in human colon cancer. In summary, this study reveals a IL-17-STEAP4-XIAP axis through which the inflammatory response induces copper uptake, promoting colon tumorigenesis.

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