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RBMS3-loss impedes TRIM21-induced ubiquitination of ANGPT2 in an RNA-independent manner and drives sorafenib resistance in hepatocellular carcinoma

Oncogene volume 44, pages 1620–1633 (2025)Cite this article

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Abstract

Sorafenib, a first-line targeted drug for advanced hepatocellular carcinoma (HCC), has limited clinical application due to intrinsic/acquired resistance. In this study, we have identified the RNA-binding protein RBMS3 as a pivotal regulator involved in sorafenib resistance among patients with HCC. Loss- and gain-of-function experiments further demonstrate that downregulation of RBMS3 promotes angiogenesis and confers resistance to sorafenib by augmenting the capacity of HCC cells to express and secrete ANGPT2, while upregulation of RBMS3 reverse these phenotypes.Through immunoprecipitation mass spectrometry experiments and co-immunoprecipitation (co-IP), we further verified that RBMS3 can facilitate the K48-linked ubiquitination and subsequent protein degradation of ANGPT2 by recruiting the ubiquitin E3 ligase TRIM21 in an RNA-independent manner.Additionally, RBMS3 is found to be deleted in HCC tissues and exhibits a significant positive correlation with angiogenesis and resistance to sorafenib treatment. Importantly, the combination of ANGPT2 antibody in RBMS3-deficient HCC cells restores sensitivity to sorafenib both in vitro and in vivo. These findings uncovered a novel molecular basis for post-translational upregulation of ANGPT2, suggesting that RBMS3-loss plays an oncogenic role in HCC by promoting angiogenesis and conferring resistance to sorafenib treatment.

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Fig. 1: RBMS3 is downregulated in HCC and correlated with sorafenib resistance.
Fig. 2: RBMS3 inhibits the angiogenesis capacity of HCC cells treated with sorafenib in vitro.
Fig. 3: RBMS3 modulates microvascular density and sorafenib sensitivity of HCC cells in vivo.
Fig. 4: RBMS3 modulates sorafenib sensitivity in HCC via suppressing ANGPT2.
Fig. 5: Ubiquitinating E3 ligase TRIM21 is essential for RBMS3-regulating ANGPT2 expression and angiogenesis in HCC.
Fig. 6: RBMS3 induced protein degradation of ANGPT2 through Lys-48-linked polyubiquitination by TRIM21.
Fig. 7: Anti-ANGPT2 sensitized RBMS3-loss HCC cells to sorafenib treatment.

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Data availability

The datasets used and/or analyzed during the current study are available from the corresponding author upon reasonable request.

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Acknowledgements

This work was supported by National Natural Science Foundation of China (No.82103637, 82303401), Guangzhou Municipal Science and Technology Project (2024A04J3475, 2025A03J3756), Joint provincial and municipal fund in Guangdong Province (2022A1515111204) and Discipline Excellence Program of Guangdong Pharmaceutical University (2024QZ06).

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Author notes

  1. These authors contributed equally: Jinrong Zhu, Lei Wang.

Authors and Affiliations

  1. Guangdong Provincial Key Laboratory of Advanced Drug Delivery, Guangdong Provincial Engineering Center of Topical Precise Drug Delivery System, School of Life Sciences and Biopharmaceutics, Guangdong Pharmaceutical University, Guangzhou, 510006, PR China

    Jinrong Zhu, Xiaoya Nie & Shengming Ou

  2. Biomedicine Research Centre, Guangdong Provincial Key Laboratory of Major Obstetric Diseases; Guangdong Provicial Clinical Research Center for Obsterics and Gynecology, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou Medical University, Guangzhou, PR China

    Jinrong Zhu, Lei Wang & Geyan Wu

  3. Department of Cardiothoracic Surgery, Taizhou Hospital of Zhejiang Province affiliated to Wenzhou Medical University, Taizhou, PR China

    Jianfei Shen

  4. Department of Oncobiology, Department of Basic Medical Sciences, Shantou University Medical College, Shantou, Guangdong, PR China

    Shuxia Zhang

  5. The Key Laboratory of Molecular Biology for High Cancer Incidence Coastal Chaoshan Area, Cancer Research Center, Shantou University Medical College, Shantou, Guangdong, PR China

    Shuxia Zhang

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Contributions

J. Zhu, G. Wu and S. Zhang supervise the project, review and editing the manuscript. S. Ou and X. Nie performed all the in vitro experiments. L. Wang conducted the molecular cloning. J. Zhu and L. Wang performed IHC assay. J. Shen provided patient tissue samples and analyzed clinical data. J. Zhu and X. Nie performed in vivo experiments. All authors read and approved the final manuscript.

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Correspondence to Shuxia Zhang or Geyan Wu.

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Zhu, J., Wang, L., Nie, X. et al. RBMS3-loss impedes TRIM21-induced ubiquitination of ANGPT2 in an RNA-independent manner and drives sorafenib resistance in hepatocellular carcinoma. Oncogene 44, 1620–1633 (2025). https://doi.org/10.1038/s41388-025-03335-x

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