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Renal NF-κB activation impairs uric acid homeostasis to promote tumor-associated mortality independent of wasting

  • Yuchen Chen
    Affiliations
    Department of Hepatobiliary and Pancreatic Surgery, Frontier Science Center for Immunology and Metabolism, Medical Research Institute, Zhongnan Hospital of Wuhan University, Wuhan University, Wuhan, Hubei 430071, China

    TaiKang Center for Life and Medical Sciences, Wuhan University, Wuhan, Hubei 430071, China
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  • Wenhao Xu
    Affiliations
    Department of Hepatobiliary and Pancreatic Surgery, Frontier Science Center for Immunology and Metabolism, Medical Research Institute, Zhongnan Hospital of Wuhan University, Wuhan University, Wuhan, Hubei 430071, China

    TaiKang Center for Life and Medical Sciences, Wuhan University, Wuhan, Hubei 430071, China
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  • Yuan Chen
    Affiliations
    Department of Hepatobiliary and Pancreatic Surgery, Frontier Science Center for Immunology and Metabolism, Medical Research Institute, Zhongnan Hospital of Wuhan University, Wuhan University, Wuhan, Hubei 430071, China

    TaiKang Center for Life and Medical Sciences, Wuhan University, Wuhan, Hubei 430071, China
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  • Anxuan Han
    Affiliations
    Department of Hepatobiliary and Pancreatic Surgery, Frontier Science Center for Immunology and Metabolism, Medical Research Institute, Zhongnan Hospital of Wuhan University, Wuhan University, Wuhan, Hubei 430071, China

    TaiKang Center for Life and Medical Sciences, Wuhan University, Wuhan, Hubei 430071, China
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  • Jiantao Song
    Affiliations
    Department of Hepatobiliary and Pancreatic Surgery, Frontier Science Center for Immunology and Metabolism, Medical Research Institute, Zhongnan Hospital of Wuhan University, Wuhan University, Wuhan, Hubei 430071, China

    TaiKang Center for Life and Medical Sciences, Wuhan University, Wuhan, Hubei 430071, China
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  • Xiaoya Zhou
    Affiliations
    Department of Hepatobiliary and Pancreatic Surgery, Frontier Science Center for Immunology and Metabolism, Medical Research Institute, Zhongnan Hospital of Wuhan University, Wuhan University, Wuhan, Hubei 430071, China

    TaiKang Center for Life and Medical Sciences, Wuhan University, Wuhan, Hubei 430071, China
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  • Author Footnotes
    3 Lead contact
    Wei Song
    Correspondence
    Corresponding author
    Footnotes
    3 Lead contact
    Affiliations
    Department of Hepatobiliary and Pancreatic Surgery, Frontier Science Center for Immunology and Metabolism, Medical Research Institute, Zhongnan Hospital of Wuhan University, Wuhan University, Wuhan, Hubei 430071, China

    TaiKang Center for Life and Medical Sciences, Wuhan University, Wuhan, Hubei 430071, China
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  • Author Footnotes
    3 Lead contact

      Highlights

      • Fly yki3SA-gut tumors cause bacterial overload via suppression of gut PGRP-SC2
      • Gut bacterial clearance increases survival of yki3SA-tumor-bearing flies
      • Renal-specific IMD-NF-κB blockade increases survival of yki3SA-tumor-bearing flies
      • Renal IMD-NF-κB blockade diminishes yki3SA-tumor-associated uric acid accumulation

      Summary

      Tumor-induced host wasting and mortality are general phenomena across species. Many groups have previously demonstrated endocrinal impacts of malignant tumors on host wasting in rodents and Drosophila. Whether and how environmental factors and host immune response contribute to tumor-associated host wasting and survival, however, are largely unknown. Here, we report that flies bearing malignant yki3SA-gut tumors exhibited the exponential increase of commensal bacteria, which were mostly acquired from the environment, and systemic IMD-NF-κB activation due to suppression of a gut antibacterial amidase PGRP-SC2. Either gut microbial elimination or specific IMD-NF-κB blockade in the renal-like Malpighian tubules potently improved mortality of yki3SA-tumor-bearing flies in a manner independent of host wasting. We further indicate that renal IMD-NF-κB activation caused uric acid (UA) overload to reduce survival of tumor-bearing flies. Therefore, our results uncover a fundamental mechanism whereby gut commensal dysbiosis, renal immune activation, and UA imbalance potentiate tumor-associated host death.

      Graphical abstract

      Keywords

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