2. Academic Validation
  3. RBM39 promotes hepatocarcinogenesis by regulating RFX1's alternative splicing and subsequent activation of integrin signaling pathway

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

  • Oncogene. 2025 Mar 3. doi: 10.1038/s41388-025-03327-x.
Bo Zhang # 1 2,  Yongjie Zhou # 3,  Xi Xu # 1,  Gang Xu 1,  Zhenru Wu 4,  Qiong Wu 1,  Qiwen Zeng 1,  Jian Yang 1,  Tao Lv 5,  Jiayin Yang 6 7
Affiliations

Affiliations

  • 1 Department of Liver Transplantation Center & Laboratory of Liver Transplantation, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China.
  • 2 Department of Critical Care Medicine, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China.
  • 3 Department of Liver Transplantation Center & Laboratory of Liver Transplantation, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China. yongjiezhou@scu.edu.cn.
  • 4 Laboratory of Pathology, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China.
  • 5 Department of Liver Transplantation Center & Laboratory of Liver Transplantation, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China. doclvtao@scu.edu.cn.
  • 6 Department of Liver Transplantation Center & Laboratory of Liver Transplantation, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China. doctoryjy@scu.edu.cn.
  • 7 Key Laboratory of Transplant Engineering and Immunology, NHC, West China Hospital, Sichuan University, Chengdu, China. doctoryjy@scu.edu.cn.
  • # Contributed equally.
PMID: 40033026 DOI: 10.1038/s41388-025-03327-x
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.

Figures
Products