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Cellular and Molecular Biology

Oncofetal SNRPE promotes HCC tumorigenesis by regulating the FGFR4 expression through alternative splicing

Abstract

Background

Due to insufficient knowledge about key molecular events, Hepatocellular carcinoma (HCC) lacks effective treatment targets. Spliceosome-related genes were significantly altered in HCC. Oncofetal proteins are ideal tumor therapeutic targets. Screening of differentially expressed Spliceosome-related oncofetal protein in embryonic liver development and HCC helps discover effective therapeutic targets for HCC.

Methods

Differentially expressed spliceosome genes were analysis in fetal liver and HCC through bioinformatics analysis. Small nuclear ribonucleoprotein polypeptide E (SNRPE) expression was detected in fetal liver, adult liver and HCC tissues. The role of SNRPE in HCC was performed multiple assays in vitro and in vivo. SNRPE-regulated alternative splicing was recognized by RNA-Seq and confirmed by multiple assays.

Results

We herein identified SNRPE as a crucial oncofetal splicing factor, significantly associated with the adverse prognosis of HCC. SOX2 was identified as the activator for SNRPE reactivation. Efficient knockdown of SNRPE resulted in the complete cessation of HCC tumorigenesis and progression. Mechanistically, SNRPE knockdown reduced FGFR4 mRNA expression by triggering nonsense-mediated RNA decay. A partial inhibition of SNRPE-induced malignant progression of HCC cells was observed upon FGFR4 knockdown.

Conclusions

Our findings highlight SNRPE as a novel oncofetal splicing factor and shed light on the intricate relationship between oncofetal splicing factors, splicing events, and carcinogenesis. Consequently, SNRPE emerges as a potential therapeutic target for HCC treatment.

Model of oncofetal SNRPE promotes HCC tumorigenesis by regulating the AS of FGFR4 pre-mRNA.

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Fig. 1: SNRPE, an oncofetal protein, is upregulated by SOX2.
Fig. 2: SNRPE promotes HCC carcinogenesis.
Fig. 3: SNRPE is required for tumorigenesis of HCCLM3 cells.
Fig. 4: SNRPE regulates the alternative splicing of FGFR4 and CREB3L4 mRNA in SMMC7721 and HCCLM3 cells.
Fig. 5: SNRPE regulates FGFR4 expression by activating NMD.
Fig. 6: The effect of FGFR4 on HCC tumorigenesis in HCC cells.
Fig. 7: FGFR4 knockdown rescues the biological effects of SNRPE-overexpressed HCC cells.

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Data availability

All data can be made available by the corresponding author upon reasonable request.

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Acknowledgements

We acknowledge the participants who generously assisted with this study. Especially, we are very grateful to Prof. Xianghuo He and Dr. Lin Huan for their help with differential alternative splicing analysis.

Funding

This work was supported by the Innovation Team Projects in Universities of Guangdong Province (grant number 2018KCXTD016 to LZ), “Double First-Class” University project (grant number CPU2018GY33 to ZJ), China Postdoctoral Science Foundation (2020M681786 to QY, 2023M740807 to QW), and the Postgraduate Research Practice Innovation Program of Jiangsu Province (KYCX20_0666 to QW).

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QW studied and designed the hypothesis and collected and analyzed data. QW wrote the first draft of the manuscript. RL received funding for the project, analyzed data, and revised the manuscript. CM and XW helped in the experiments. CM and LL helped establish the animal model. MH designed the study and revised the manuscript. LS and ZY revised the manuscript. ZJ, LZ, and QY received funding for the project, supervised the execution of the project, helped in designing the study, analyzed the results, and revised the manuscript. All authors reviewed the results and approved the final version of the manuscript.

Corresponding authors

Correspondence to Zhenzhou Jiang, Luyong Zhang or Qinwei Yu.

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All animal experiments followed the instructions of the Animal Care Committee of China Pharmaceutical University (Approval No. 2021-10-021).

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Wu, Q., Liao, R., Miao, C. et al. Oncofetal SNRPE promotes HCC tumorigenesis by regulating the FGFR4 expression through alternative splicing. Br J Cancer (2024). https://doi.org/10.1038/s41416-024-02689-5

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