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Cellular and Molecular Biology

Deciphering the role of IGF2BP2 and PRMT5 in gallbladder cancer progression: insights from multi-omics analysis

British Journal of Cancer (2025)Cite this article

Subjects

Abstract

Background

Gallbladder cancer (GBC) is a highly aggressive malignancy with limited therapeutic options and a poor prognosis. Elucidating the molecular mechanisms driving GBC progression is essential for identifying novel therapeutic targets.

Methods

Single-cell transcriptomics, high-throughput sequencing, and proteomics techniques were employed to investigate the role of the IGF2BP2-PRMT5 axis in GBC. Functional assays were conducted to assess cell proliferation, invasion, and migration, while mechanistic studies examined the impact of N6-methyladenosine (m6A) modifications and downstream signalling pathways. Furthermore, a humanised mouse model was utilised to examine the impact of this axis on immune cell infiltration and tumour immune evasion.

Results

IGF2BP2 was found to stabilise PRMT5 expression via m6A modifications, thereby promoting GBC cell proliferation, invasion, and migration. Mechanistically, PRMT5 activated the AKT/mTOR pathway, upregulated SREBP1, and reprogrammed lipid metabolism, leading to increased lipid synthesis and accumulation. Functional assays and in vivo experiments revealed that modulation of the IGF2BP2-PRMT5 axis significantly influenced immune cell infiltration, fostering immune evasion.

Conclusions

The IGF2BP2-PRMT5 axis is critical in GBC progression by orchestrating metabolic reprogramming and immune modulation. Targeting this axis holds potential as a therapeutic strategy for combating GBC.

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Fig. 1: Single-cell sequencing reveals the immune inhibitory microenvironment in GBC.
Fig. 2: High-throughput sequencing results reveal significantly higher expression of IGF2BP2 in GBC tissue.
Fig. 3: The impact of IGF2BP2 on GBC proliferation, invasion, and migration in terms of silence/expression.
Fig. 4: The role of IGF2BP2 in GBC immunosuppression.
Fig. 5: IGF2BP2 stabilises PRMT5 through m6A modification.
Fig. 6: Effect of PRMT5 overexpression on reversing the silencing effect of IGF2BP2.
Fig. 7: The impact of PRMT5 on lipid metabolism in GBC cells.
Fig. 8: Impact of PRMT5 on the expression of fatty acid synthase via upregulation of SREBP1.
Fig. 9: Impact of PRMT5 on lipid metabolism via activation of the AKT/mTOR signalling pathway.
Fig. 10: Impact of PRMT5 on the proliferation, invasion, and migration of GBC cells via the AKT/mTOR axis.
Fig. 11: The impact of PRMT5 on GBC immune evasion through the AKT/mTOR axis upregulating SREBP1.
Fig. 12

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Data availability

All data generated or analysed during this study are included in this article and/or its supplementary material files. Further enquiries can be directed to the corresponding author.

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Funding

This study was supported by the Key Research and Development Project of Sichuan Province (2023YFS0171).

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Author notes

  1. These authors contributed equally: Xinwei Yang, Lingqi Sun.

Authors and Affiliations

  1. Department of Biliary Surgery IV, Eastern Hepatobiliary Surgery Hospital, Naval Military Medical University, Shanghai, China

    Xinwei Yang

  2. Sleep Medicine Center, Mental Health Center, West China Hospital, Sichuan University, Chengdu, Sichuan, China

    Lingqi Sun

  3. Division of Medical Oncology, Cancer Center, West China Hospital, Sichuan University, Chengdu, PR China

    Jiamin Guo, Yichen Zheng, Tonghui Ren, Lingnan Zheng & Ji Ma

  4. Department of Breast Surgery, The 940 Hospital of the Joint Logistics Support Force of the Chinese People’s Liberation Army, Lanzhou, PR China

    Ying Liu

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Contributions

XY and LS contributed equally to this work and were responsible for study design, data acquisition, and manuscript drafting. JG, YZ, and TR performed bioinformatics analyses, including single-cell transcriptomics and high-throughput sequencing data interpretation. YL and LZ conducted functional assays and mechanistic studies to elucidate the role of the IGF2BP2-PRMT5 axis in gallbladder cancer progression. JM supervised the study, provided critical revisions, and finalised the manuscript. All authors read and approved the final version of the manuscript.

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Correspondence to Ji Ma.

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The authors declare no competing interests.

Ethical statement

All methods in this study were performed in accordance with the relevant guidelines and regulations. All animal experiments were approved by the Animal Ethics Committee of West China Hospital, Sichuan University (Approval No. 20240103003). Human sample collection and related procedures were approved by the Ethics Committee of West China Hospital, Sichuan University (Approval No. 2023699), and informed consent was obtained from all participants prior to inclusion in the study.

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Yang, X., Sun, L., Guo, J. et al. Deciphering the role of IGF2BP2 and PRMT5 in gallbladder cancer progression: insights from multi-omics analysis. Br J Cancer (2025). https://doi.org/10.1038/s41416-025-03062-w

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