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PABPN1-C5 axis promotes hepatocellular carcinoma progression via NF-κB activation

Oncogene volume 44, pages 3512–3524 (2025)Cite this article

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Abstract

RNA polyadenylation is a key post-transcriptional modification essential for gene expression regulation. However, the role and mechanism of polyadenylation and its key molecule, polyadenylate binding protein nuclear 1 (PABPN1), in hepatocellular carcinoma (HCC) remain poorly understood. This study investigates the role of PABPN1 and its regulatory genes in HCC progression to identify potential therapeutic targets. Analysis of The Cancer Genome Atlas (TCGA) dataset and an independent HCC cohort revealed significant upregulation of PABPN1 in HCC patients, which correlates with poor prognosis. Loss-of-function studies using HCC cell lines and conditional knockout mouse models demonstrated that targeting PABPN1 inhibited HCC progression. Conversely, overexpression of PABPN1 promoted HCC development in vitro and in a hydrodynamic transfection hepatocarcinogenesis mouse model. Mechanistic investigations showed that PABPN1 modulates C5 mRNA polyadenylation and stability, with the PABPN1-C5 axis driving NF-κB activation and recruiting polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs) to promote HCC progression. Therapeutic targeting of the PABPN1-C5 axis using the C5a receptor inhibitor CCX168 significantly inhibited HCC progression in both in vitro and in vivo models. This study identifies PABPN1 as a critical regulator of HCC development and sheds light on the post-transcriptional regulation of complement components in cancer. Targeting the PABPN1-C5 axis represents a promising strategy for HCC treatment.

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Fig. 1: PABPN1 is upregulated in HCC and associated with poor prognosis.
Fig. 2: PABPN1 knockout suppresses HCC progression in vitro and in vivo.
Fig. 3: PABPN1 overexpression promotes HCC tumorigenesis.
Fig. 4: C5 is the downstream target of PABPN1 in HCC.
Fig. 5: PABPN1–C5 axis activates NF-κB signaling and promotes PMN-MDSC recruitment in HCC.
Fig. 6: C5 mediates the oncogenic function of PABPN1 in HCC.
Fig. 7: Targeting PABPN1-C5 with CCX168 inhibits HCC progression in vivo.

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Data availability

The public data re-analyzed in our study was TCGA-HCC dataset. The RNA sequencing data of PABPN1 knockdown and its corresponding control HCC cells have been publicly deposited at Gene Expression Omnibus (GEO accession number: GSE289702). The data supporting the findings of this study are available from the corresponding author upon reasonable request.

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Acknowledgements

This work was funded by National Key Research and Development Program of China (2023YFA1800804 to SL, 2022YFE0138700 to SL, 2022YFA1105300 to SL), National Natural Science Foundation of China (82325036 to SL, 82201734 and 82472753 to CZ, 82200954 to JM), Fundamental Research Funds for the Central Universities, Sun Yat-sen University (23ykzy004 to SL).

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Author notes

  1. These authors contributed equally: Siyao Guo, Qiang Zhang.

Authors and Affiliations

  1. Department of Laboratory Medicine, Sun Yat-sen University, Guangzhou, China

    Siyao Guo

  2. Center for Translational Medicine, Precision Medicine Institute, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China

    Siyao Guo, Qiang Zhang, Jieyi Ma, Zhaoyu Wang, Siyi Zheng, Hongshen Qiu, Shuibin Lin & Canfeng Zhang

  3. Laboratory of General Surgery, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China

    Jieyi Ma

  4. Department of Musculoskeletal Oncology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China

    Yutong Zou

  5. Department of Life Science, College of Natural Sciences, Hanyang University, Seoul, Republic of Korea

    Junho Choe

  6. Hanyang Institute of Bioscience and Biotechnology, Hanyang University, Seoul, Republic of Korea

    Junho Choe

  7. Research Institute for Natural Sciences, Hanyang University, Seoul, Republic of Korea

    Junho Choe

  8. Research Institute for Convergence of Basic Sciences, Hanyang University, Seoul, Republic of Korea

    Junho Choe

  9. State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, Guangzhou, China

    Shuibin Lin

  10. Innovative Cancer Research Center, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, Guangdong, China

    Shuibin Lin

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Contributions

SG and CZ designed the protocol of this study. QZ and JM performed in vitro assays. SG, YZ, ZW and SZ performed in vivo assays. All other data analysis was performed by SG, HQ, CZ and JC. SG, CZ and SL wrote the paper and all authors reviewed the final manuscript.

Corresponding authors

Correspondence to Shuibin Lin or Canfeng Zhang.

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The authors declare no competing interests.

Ethical approval

All human specimens were approved by the Ethics Committee of the First Affiliated Hospital of Sun Yat-sen University (Approved No: [2020]356 and [2022]180). We have obtained patients’ informed consent for publication. All animal experiments were approved by the Institutional Care and Animal Use Committee of the First Affiliated Hospital of Sun Yat-sen University (Approval No [2023]147). All methods were performed in accordance with the relevant guidelines and regulations.

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Guo, S., Zhang, Q., Ma, J. et al. PABPN1-C5 axis promotes hepatocellular carcinoma progression via NF-κB activation. Oncogene 44, 3512–3524 (2025). https://doi.org/10.1038/s41388-025-03501-1

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