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Androgen receptor promotes arachidonic acid metabolism and angiogenic microenvironment in AFP-negative hepatocellular carcinoma

Author

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  • Zhilong Lin

    (The First Affiliated Hospital of Sun Yat-sen University)

  • Xiaofei Liu

    (Sun Yat-sen University)

  • Houwei Wang

    (The First Affiliated Hospital of Sun Yat-sen University)

  • Shumin Li

    (Sun Yat-sen University)

  • Ziqiang Miao

    (Sun Yat-sen University)

  • Jing Yang

    (Sun Yat-sen University)

  • Yuting Zhang

    (Sun Yat-sen University)

  • Kai Lei

    (The First Affiliated Hospital of Sun Yat-sen University)

  • Yifan Wu

    (Sun Yat-sen University)

  • Youmei Kang

    (Sun Yat-sen University)

  • Ruoyin Zheng

    (The First Affiliated Hospital of Sun Yat-sen University)

  • Zonglin Xie

    (Sun Yat-sen University)

  • Yixi Wen

    (Sun Yat-sen University)

  • Xiaoxue Ren

    (Sun Yat-sen University)

  • Chunxiao Liu

    (Sun Yat-sen University)

  • Alfred Sze-Lok Cheng

    (The Chinese University of Hong Kong)

  • Yubin Xie

    (Sun Yat-sen University)

  • Shuling Chen

    (Sun Yat-sen University
    Sun Yat-sen University)

  • Ming Kuang

    (The First Affiliated Hospital of Sun Yat-sen University
    Sun Yat-sen University)

  • Sui Peng

    (Sun Yat-sen University
    Sun Yat-sen University
    Sun Yat-sen University)

  • Zhenwei Peng

    (Sun Yat-sen University
    The First Affiliated Hospital of Sun Yat-sen University)

  • Zihao Dai

    (The First Affiliated Hospital of Sun Yat-sen University)

Abstract

Alpha-fetoprotein (AFP) is a classic biomarker for hepatocellular carcinoma (HCC). AFP-positive HCC (AFP+ HCC) has been intensively investigated; however, the genomic, transcriptomic and microenvironmental characteristics of AFP-negative HCC (AFP− HCC) remain to be deciphered. Here we show that tumors display mild differences in genetic alterations between AFP− HCC and AFP+ HCC patients, while AFP− HCC exhibits hyperactive arachidonic acid metabolism. Furthermore, the transcription activity of androgen receptor (AR) is significantly increased in AFP− HCC and plays a positive regulatory role in arachidonic acid metabolism and its metabolite 11,12-epoxyeicosatrienoic acid (11,12-EET). The tumor-derived 11,12-EET exhibits high affinity for EGFR that promotes the migration and tube formation of endothelial cells in vitro. Combination of lenvatinib and bicalutamide (an AR antagonist) enhances the therapeutic efficacy for AFP− HCC. Overall, we uncover the AR-mediated hyperactive arachidonic acid metabolism in AFP− HCC, and reveal AR-11,12-EET-EGFR axis-induced angiogenesis, providing a promising strategy of combined AR antagonist with lenvatinib for AFP− HCC treatment.

Suggested Citation

  • Zhilong Lin & Xiaofei Liu & Houwei Wang & Shumin Li & Ziqiang Miao & Jing Yang & Yuting Zhang & Kai Lei & Yifan Wu & Youmei Kang & Ruoyin Zheng & Zonglin Xie & Yixi Wen & Xiaoxue Ren & Chunxiao Liu & , 2025. "Androgen receptor promotes arachidonic acid metabolism and angiogenic microenvironment in AFP-negative hepatocellular carcinoma," Nature Communications, Nature, vol. 16(1), pages 1-20, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-61448-z
    DOI: 10.1038/s41467-025-61448-z
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