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RBM12 drives PD-L1-mediated immune evasion in hepatocellular carcinoma by increasing JAK1 mRNA translation

Oncogene volume 43, pages 3062–3077 (2024)Cite this article

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Abstract

Immunosuppression characterizes the tumour microenvironment in HCC, and recent studies have implicated RNA-binding proteins (RBPs) in the development of HCC. Here, we conducted a screen and identified RBM12 as a key protein that increased the expression of PD-L1, thereby driving immune evasion in HCC. Furthermore, RBM12 was found to be significantly upregulated in HCC tissues and was associated with a poor prognosis for HCC patients. Through various molecular assays and high-throughput screening, we determined that RBM12 could directly bind to the JAK1 mRNA via its 4th-RRM (RNA recognition motif) domain and recruit EIF4A2 through its 2nd-RRM domain, enhancing the distribution of ribosomes on JAK1 mRNA, which promotes the translation of JAK1 and the subsequent upregulation of its expression. As a result, the activated JAK1/STAT1 pathway transcriptionally upregulates PD-L1 expression, facilitating immune evasion in HCC. In summary, our findings provide insights into the significant contribution of RBM12 to immune evasion in HCC, highlighting its potential as a therapeutic target in the future.

This graphical abstract shows that elevated expression of RBM12 in HCC can augment PD-L1-mediated tumour immune evasion by increasing the efficiency of JAK1 mRNA translation.

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Fig. 1: RBM12 upregulates the expression of programmed death-ligand 1 (PD-L1) in hepatocellular carcinoma (HCC).
Fig. 2: RBM12 is highly expressed in HCC and negatively correlated with the patient prognosis.
Fig. 3: RBM12 promotes HCC immune evasion by increasing the activity of the JAK1/STAT1 signalling pathway.
Fig. 4: RBM12 recruits EIF4A2 to increase the translation of JAK1.
Fig. 5: RBM12 forms a heterodimer with EIF4A2 through the 2nd RRM domain to increase the translation of JAK1.
Fig. 6: RBM12-EIF4A2 synergistically increase PD-L1 expression in HCC.
Fig. 7: Knockout of RBM12 enhances the efficacy of HCC immunotherapy.

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Data availability

All data associated with this study are presented in the paper or Supplementary Data. Materials supporting the findings of this study are available from the corresponding author upon reasonable request. The high-throughput sequencing data generated in this study are publicly available at SRA datebase (PRJNA1067431).

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Acknowledgements

We sincerely thank the central Laboratory of Taizhou People’s Hospital Affiliated to Nanjing Medical University for the help of instruments and equipment.

Funding

This project was supported by The Youth Fund of Taizhou People’s Hospital Affiliated to Nanjing Medical University (TZKY20220102), Key research project of Taizhou School of Clinical Medicine, Nanjing Medical University (TZKY20230306), Scientific research start-up fund of Taizhou People’s Hospital (QDJJ202106, QDJJ202103), Taizhou Society Development Project, Jiangsu, China (TS202308), General Project of Jiangsu Provincial Health Commission (H2023030), National Natural Science Foundation of China (82372755, 82203728, 82372746, 82374223), Huzhou Municipal Science and Technology Bureau welfare applied research project (Grant No. 2021GZ69), Research Fund of Anhui Institute of translational medicine (2022zhyx-C21), Outstanding Youth Scientific Research Projects in colleges and universities of Anhui Province (2022AH030115) and Nanjing special foundation for health science and technology development (distinguished young program, JQX21005).

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Author notes

  1. These authors contributed equally: Hexu Han, Qian Shi, Yue Zhang, Mingdong Ding, Xianzhong He.

Authors and Affiliations

  1. Department of Gastroenterology, The Affiliated Taizhou People’s Hospital of Nanjing Medical University, Taizhou School of Clinical Medicine, Nanjing Medical University, Taizhou, Jiangsu, 225300, China

    Hexu Han, Cuixia Liu, Dakun Zhao, Yifan Wang & Yanping Du

  2. Huzhou Key Laboratory of Translational Medicine, The First Affliated Hospital of Huzhou University, Huzhou, Zhejiang, 313000, China

    Qian Shi

  3. Clinical Medical Laboratory Center, The Affiliated Taizhou People’s Hospital of Nanjing Medical University, Taizhou, Jiangsu, 225300, China

    Yue Zhang

  4. Department of Infectious Diseases, The Affiliated Taizhou People’s Hospital of Nanjing Medical University, Taizhou School of Clinical Medicine, Nanjing Medical University, Taizhou, Jiangsu, 225300, China

    Mingdong Ding

  5. Department of Hepatobiliary Surgery, The First Affiliated Hospital of Anhui Medical University, Innovative Institute of Tumor Immunity and Medicine (ITIM), Anhui Provincial Innovation Institute for Pharmaceutical Basic Research, Anhui Province Key Laboratory of Tumor Immune Microenvironment and Immunotherapy, Hefei, Anhui, 230000, China

    Xianzhong He & Qiang Wang

  6. Department of Hepatobiliary Surgery, The Affiliated Taizhou People’s Hospital of Nanjing Medical University, Taizhou School of Clinical Medicine, Nanjing Medical University, Taizhou, Jiangsu, 225300, China

    Yichao Zhu & Yin Yuan

  7. Department of pharmacy, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, 210000, China

    Siliang Wang

  8. Department of Gastroenterology, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, 210000, China

    Huimin Guo

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Contributions

Qiang Wang, Huimin Guo and Hexu Han performed study concept and design; Hexu Han and Qian Shi completed the experimental part of the project; Yue Zhang, Mingdong Ding and Xianzhong He performed development of methodology and writing, review and revision of the paper; Yin Yuan and Siliang Wang provided acquisition, analysis and interpretation of data, and statistical analysis; Cuixia Liu, Dakun Zhao, Yifan Wang and Yanping Du provided technical and material support. All authors read and approved the final paper.

Corresponding authors

Correspondence to Yin Yuan, Siliang Wang, Huimin Guo or Qiang Wang.

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The authors declare no competing interests.

Ethics approval

Three cohorts of HCC tissue samples were collected from the Affiliated Taizhou People’s Hospital of Nanjing Medical University (Jiangsu Province, China), and the experimental protocol was approved by the Institutional Ethics Review Board of the Affiliated Taizhou People’s Hospital of Nanjing Medical University (2022-008-01). Pathological analysis was conducted to validate the authenticity of the specimens. Animal ethical testing certificates were approved by the Experimental Center of Jiangsu Hanjiang Biotechnology Co., LTD (HJSW-23050302), and the animals were raised in accordance with animal welfare laws.

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Han, H., Shi, Q., Zhang, Y. et al. RBM12 drives PD-L1-mediated immune evasion in hepatocellular carcinoma by increasing JAK1 mRNA translation. Oncogene 43, 3062–3077 (2024). https://doi.org/10.1038/s41388-024-03140-y

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