Androgen receptor promotes arachidonic acid metabolism and angiogenic microenvironment in AFP-negative hepatocellular carcinoma
Alpha-fetoprotein (AFP) is a classic biomarker for hepatocellular carcinoma (HCC). AFP-positive HCC (AFP<sup>+</sup> HCC) has been intensively investigated; however, the genomic, transcriptomic and microenvironmental characteristics of AFP-negative HCC (AFP<sup>-</sup> HCC) remain to be deciphered. Here we show that tumors display mild differences in genetic alterations between AFP<sup>-</sup> HCC and AFP<sup>+</sup> HCC patients, while AFP<sup>-</sup> HCC exhibits hyperactive arachidonic acid metabolism. Furthermore, the transcription activity of androgen receptor (AR) is significantly increased in AFP<sup>-</sup> 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<sup>-</sup> HCC. Overall, we uncover the AR-mediated hyperactive arachidonic acid metabolism in AFP<sup>-</sup> HCC, and reveal AR-11,12-EET-EGFR axis-induced angiogenesis, providing a promising strategy of combined AR antagonist with lenvatinib for AFP<sup>-</sup> HCC treatment.
Authors
- Yifan Wu (ORCID: https://orcid.org/0000-0002-6179-0494)
- Yubin Kang (ORCID: https://orcid.org/0000-0001-6678-8732)
- Yubing Wen (ORCID: https://orcid.org/0000-0003-0438-8447)
- Kai Lei (ORCID: https://orcid.org/0000-0002-1548-6862)
- Ruoyin Zheng
- Zhenwei Peng (ORCID: https://orcid.org/0000-0002-0617-3805)
- Zihao Dai (ORCID: https://orcid.org/0000-0002-8921-2389)
- Jing Yang (ORCID: https://orcid.org/0000-0001-9653-5541)
- Sui Peng (ORCID: https://orcid.org/0000-0002-7399-2579)
- Yubin Xie (ORCID: https://orcid.org/0000-0002-3566-4849)
- Ming Kuang (ORCID: https://orcid.org/0000-0002-7397-5779)
- Zonglin Xie (ORCID: https://orcid.org/0000-0003-4133-7163)
- Zhihao Lin (ORCID: https://orcid.org/0009-0003-7158-4787)
- Ziqiang Miao
- Xiaoxue Ren (ORCID: https://orcid.org/0000-0001-5869-1797)
- Xiaofei Liu (ORCID: https://orcid.org/0000-0001-7524-485X)
- Shumin Li (ORCID: https://orcid.org/0000-0001-8083-1071)
- Yuting Zhang (ORCID: https://orcid.org/0000-0003-4204-9091)
- Alfred Sze‐Lok Cheng
- Chunxiao Liu (ORCID: https://orcid.org/0000-0002-8677-1943)
- Haoming Wang
Institutions
- Sun Yat-sen University (CN)
- Chinese University of Hong Kong (HK)
- The First Affiliated Hospital, Sun Yat-sen University (CN)
- Sun Yat-sen University Cancer Center (CN)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-07-12
- DOI
- https://doi.org/10.1038/s41467-025-61448-z
- Citations
- 5
- Primary Topic
- Cancer, Hypoxia, and Metabolism
- Type
- article
- Field-Weighted Citation Impact
- 4.68
Funders
- National Natural Science Foundation of China
- National Science Fund for Distinguished Young Scholars