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DDX39B facilitates the malignant progression of hepatocellular carcinoma via activation of SREBP1-mediated de novo lipid synthesis

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Abstract

Purpose

The detailed molecular mechanisms of aberrant lipid metabolism in HCC remain unclear. Herein, we focused on the potential role of DDX39B in aberrant lipogenesis and malignant development in HCC.

Methods

DDX39B expression in HCC and para-cancer tissues was measured by immunohistochemistry. CCK-8, colony formation and Transwell assays were utilized to detect HCC cell proliferation, migration and invasion in vitro. Oil red O and Nile red staining and triglyceride and cholesterol detection were used to measure lipogenesis. Coimmunoprecipitation was used to detect interactions between DDX39B and SREBP1. Immunofluorescence assays were performed to investigate the impact of DDX39B on SREBP1 nuclear translocation. A luciferase assay was used to explore the transcriptional activity of SREBP1. The subcutaneous and orthotopic xenograft models in nude mice were generated to verify the contribution of the DDX39B/SREBP1 axis to tumor growth, lung metastasis and lipid synthesis in vivo.

Results

DDX39B is upregulated in HCC tissues and predicts a worse prognosis. Upregulated DDX39B contributes to the proliferation, metastasis and lipogenesis of HCC cells. Mechanistically, DDX39B directly interacts with SREBP1, and silencing DDX39B impairs the stabilization of the SREBP1 protein through FBXW7-mediated ubiquitination and degradation of SREBP1. Furthermore, DDX39B deficiency decreases the nuclear translocation and activation of SREBP1 and transcription of SREBP1 downstream genes, resulting in reduced lipid accumulation.

Conclusions

Our study reveals a novel mechanism by which DDX39B facilitates the malignant progression of HCC via activation of SREBP1-mediated de novo lipogenesis, implicating DDX39B as both a potential predictor of recurrence and prognosis and a promising therapeutic target.

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Data availability

All data generated or analyzed during this study are included in this manuscript (and its supplementary information files) or available from the corresponding author upon reasonable request.

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Funding

This work was supported by the National Natural Science Foundation of China (82072933, 82272892, and 82103525); 1·3·5 project for disciplines of excellence Clinical Research Incubation Project, West China Hospital, Sichuan University (2020HXFH007); and Department of Science and Technology of Sichuan Province (2022YFS0216).

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  1. Kai Li & Ping Lin

    Present address: Hi-Tech Development, 1# Keyuan 4 Road, Gaopeng Avenue, Chengdu, Sichuan, 610041, People’s Republic of China

  2. Tianyu Feng, Siqi Li and Gang Zhao contributed equally.

Authors and Affiliations

  1. Division of Abdominal Tumor Multimodality Treatment, Cancer Center and Lab of Experimental Oncology, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan Province, China

    Tianyu Feng, Siqi Li, Gang Zhao, Qin Li, Hang Yuan, Jie Zhang, Rui Gu, Deqiong Ou, Yafei Guo, Qiming Kou, Qijing Wang, Kai Li & Ping Lin

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Contributions

LP, LK and FTY conceived this work; LK and FTY designed the experiments. FTY, LSQ and ZG developed the methodology, performed in vitro and in vivo experiments and analyzed the data; LQ, YH, ZJ, GR and ODQ contributed to the in vivo experiments; GYF, KQM and WQJ prepared Table 1 and Table 2; FTY and LK wrote the manuscript; LK and LP revised the manuscript. LP supervised this work. All authors reviewed the manuscript.

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Correspondence to Kai Li or Ping Lin.

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Informed consent was obtained from patients, and this study was approved by the Ethics Committee of Shanghai Outdo Biotech Company. Animal studies were conducted with approval from the Institutional Animal Care and Use Committee of West China Hospital Sichuan University.

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Feng, T., Li, S., Zhao, G. et al. DDX39B facilitates the malignant progression of hepatocellular carcinoma via activation of SREBP1-mediated de novo lipid synthesis. Cell Oncol. 46, 1235–1252 (2023). https://doi.org/10.1007/s13402-023-00807-8

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