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RBM39 promotes hepatocarcinogenesis by regulating RFX1’s alternative splicing and subsequent activation of integrin signaling pathway

Oncogene volume 44, pages 1488–1503 (2025)Cite this article

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Abstract

Alternative splicing (AS) is crucial for tumor cells as it regulates protein expression and produces various protein isoforms, which can have diverse or even opposing roles in tumor growth and metastasis. Despite its significance, the role of AS and related splicing factors, particularly splicing-related messenger ribonucleoproteins (mRNPs), in hepatocarcinogenesis, is poorly understood. High-throughput transcriptome sequencing of HCC patients revealed that the spliceosome pathway might play a significant role in HCC development. Through the combined analysis of the three gene clusters, the splicing factor RBM39 was identified, which was highly expressed in HCC tumor tissues with prognostic value. Functional studies showed that silencing RBM39 inhibited cell proliferation, migration, and invasion via the integrin pathway. By performing RNA immunoprecipitation sequencing (RIP-seq), we found that RBM39 combined to RFX1 pre-mRNA and regulated alternative splicing of exon 2. Mechanistically, the exon 2 skipping in RFX1, influenced by high RBM39 expression in HCC cells, led to the production of an N-terminal truncated RFX1, which lost the transcriptional repression ability on oncogenic collagen genes. High RBM39 expression enhances the malignant capabilities of HCC cells by regulating the alternative splicing of RFX1 and subsequently activating the FAK/PI3K/AKT signaling pathway.

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Fig. 1: The spliceosome pathway is enriched in HCC and RBM39 is positively correlated with poor HCC prognosis.
Fig. 2: Knockdown of RBM39 inhibits proliferation and metastasis in HCC cells.
Fig. 3: Knockdown of RBM39 alters the expression of collagen and integrin genes that influence the FAK/PI3K/AKT signaling pathway.
Fig. 4: RBM39 interacts with RFX1 and regulates the alternative splicing of RFX1.
Fig. 5: Effects of RFX1-s and RFX1-FL isoforms on proliferation, migration and invasion of HCC cells.
Fig. 6: Reduction the proportion of RFX1-FL “rescues” the malignancy capacity of HCC cells with low RBM39 expression.
Fig. 7: Knockdown of RBM39 suppresses HCC progression in mouse models.
Fig. 8: Differences in gene and protein expression in HCC patients with low and high RBM39 expression.

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Data availability

All data needed to evaluate the conclusions in the paper are present in the paper and the Supplementary Materials. The data underlying this article are available in the Gene Expression Omnibus, and can be accessed under accession codes GSE275347 and GSE275496.

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Acknowledgements

This work was supported by grants from the National Key Research and Development Program of China (2023YFC2505900 & 2022YFC2304705), the Natural Science Foundation of China (82173255, 82273330, 82270691), 1.3.5 project for disciplines of excellence from West China Hospital of Sichuan University (No. ZYGD24002), the Key R&D projects of Sichuan Provincial Department of Science and Technology (23ZDYF2182, 23ZDYF2083). We thank http://www.bioinformatics.com.cn/ for plotting part of pictures. We acknowledge the support provided by LC-Bio Technologies (Hangzhou) Co., Ltd. with the RNA sequencing and data analysis. We acknowledge the support provided by SEQHEALTH (Wuhan) Co., Ltd. with the RIP sequencing and data analysis.

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  1. These authors contributed equally: Bo Zhang, Yongjie Zhou, Xi Xu.

Authors and Affiliations

  1. Department of Liver Transplantation Center & Laboratory of Liver Transplantation, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China

    Bo Zhang, Yongjie Zhou, Xi Xu, Gang Xu, Qiong Wu, Qiwen Zeng, Jian Yang, Tao Lv & Jiayin Yang

  2. Department of Critical Care Medicine, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China

    Bo Zhang

  3. Laboratory of Pathology, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China

    Zhenru Wu

  4. Key Laboratory of Transplant Engineering and Immunology, NHC, West China Hospital, Sichuan University, Chengdu, China

    Jiayin Yang

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Contributions

B.Z., X.X., Q.W.Z., and Z.R.W.: performed the experiments and generated data. B.Z., X.X., Y.J.Z., and J.Y.Y.: analyzed the data. B.Z., Y.J.Z., G.X., T.L., and J.Y.Y.: designed the experiments. B.Z. and Y.J.Z.: wrote the manuscript. G.X., Q.W., T.L., and J.Y.: provided clinical samples. All authors have read and approved the final manuscript.

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Correspondence to Yongjie Zhou, Tao Lv or Jiayin Yang.

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The authors confirm that all methods were performed in accordance with the relevant guidelines and regulations. All animal experiments were approved by the Experimental Animal Care Committee of West China Hospital of Sichuan University (approval number: 20230228051). The use of patient specimens and the relevant database were approved by the Research Ethics Committee of West China Hospital of Sichuan University (approval number: 2020-166).

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Zhang, B., Zhou, Y., Xu, X. et al. RBM39 promotes hepatocarcinogenesis by regulating RFX1’s alternative splicing and subsequent activation of integrin signaling pathway. Oncogene 44, 1488–1503 (2025). https://doi.org/10.1038/s41388-025-03327-x

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