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.

中文翻译：

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炎症通过 IL-17-STEAP4-XIAP 轴动员铜代谢以促进结肠肿瘤发生。

已知铜水平在发炎和恶性组织中升高。但这种选择性富集的机制一直难以捉摸。在这项研究中，我们报告了一个轴，炎症细胞因子（如 IL-17）通过诱导金属还原酶 STEAP4 驱动细胞铜摄取。IL-17 诱导的细胞内铜水平升高会导致 E3 连接酶 XIAP 的激活，从而增强 IL-17 诱导的 NFκB 激活并抑制半胱天冬酶 3 的活性。重要的是，这种 IL-17 诱导的 STEAP4 依赖性细胞铜摄取对于结肠炎相关肿瘤发生的小鼠模型中的结肠肿瘤形成至关重要，并且 STEAP4 表达与人结肠癌中的 IL-17 水平和 XIAP 激活相关。总之，