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BEX1 supports the stemness of hepatoblastoma by facilitating Warburg effect in a PPARγ/PDK1 dependent manner

British Journal of Cancer (2023)Cite this article

Subjects

Abstract

Background

Hepatoblastoma (HB) is a highly aggressive paediatric malignancy that exhibits a high presence of cancer stem cells (CSCs), which related to tumour recurrence and chemotherapy resistance. Brain expressed X-linked protein 1 (BEX1) plays a pivotal role in ciliogenesis, axon regeneration and differentiation of neural stem cells. However, the role of BEX1 in metabolic and stemness programs in HB remains unclear.

Methods

BEX1 expression in human and mouse HB was analyzed using gene expression profile data from NCBI GEO and immunohistochemical validation. Seahorse extracellular flux analyzer, ultra-high-performance liquid-chromatography mass spectrometry (LC-MS), flow cytometry, qRT-PCR, Western Blot, sphere formation assay, and diluted xenograft tumour formation assay were used to analyze metabolic and stemness features.

Results

Our results indicated that overexpression of BEX1 significantly enhanced the Warburg effect in HB cells. Furthermore, glycolysis inhibition largely attenuated the effects of BEX1 on HB cell growth and self-renewal, suggesting that BEX1 promotes stemness maintenance of HB cells by regulating the Warburg effect. Mechanistically, BEX1 enhances Warburg effect through the downregulation of peroxisome proliferator-activated receptor-gamma (PPARγ). Furthermore, pyruvate dehydrogenase kinase isozyme 1 (PDK1) is required for PPARγ-induced inhibition of Warburg effect in HB. In addition, BEX1 supports the stemness of HB by enhancing Warburg effect in a PPARγ/PDK1 dependent manner.

Conclusions

HB patients with high BEX1 and PDK1 expression had a poor prognosis. BEX1 promotes the stemness maintenance of HB cells via modulating the Warburg effect, which depends on PPARγ/PDK1 axis. Pioglitazone could be used to target BEX1-mediated stemness properties in HB by upregulating PPARγ.

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Fig. 1: BEX1 overexpression promotes the self-renewal of HB cells.
Fig. 2: Glycolysis is a metabolic programme preferred by mouse HB cells.
Fig. 3: BEX1 regulates glycolysis in HB cells.
Fig. 4: BEX1 promotes the stemness maintenance of HB cells via modulating the Warburg effect.
Fig. 5: BEX1 enhances Warburg effect via downregulating PPARγ in HB.
Fig. 6: PDK1 is required for PPARγ -induced inhibition of Warburg effect in HB cells.
Fig. 7: BEX1 enhances the stemness maintenance of HB cells in a PPARγ/PDK1 dependent manner.
Fig. 8: BEX1 positively correlates with PDK1 in HB patients.

Data availability

All of the relevant data are included in supplemental information. RNA-seq data have been submitted to the SRA database (SRA: PRJNA721822). All data are available upon request to the corresponding authors.

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Acknowledgements

We thank Professor Xin Chen and Professor Perry Hackett for providing the plasmids. The schematic diagram in this article was drawn by Figdraw. We thank Ms. Jie Chen for her help in designing the schematic diagram.

Funding

This work was supported by grants from the National Natural Science Foundation of China (No. 82103664), Joint Construction Project of Henan Medical Science and Technology (LHGJ20200281) and Guangzhou Basic and Applied Basic Research Project (No. 202102021274).

Author information

Author notes

  1. These authors contributed equally: Qian Wang, Ning Liang, Chaoxu Liu, Jing Li.

Authors and Affiliations

  1. Department of General Surgery, Tangdu Hospital, Air Force Military Medical University, Xi’an, 710032, China

    Qian Wang, Xianli He & Gang Wang

  2. Department of General Surgery, The First Affiliated Hospital, Zhengzhou University, Zhengzhou, 450052, China

    Qian Wang

  3. Department of General Surgery, The 75th Group Army Hospital, Dali, 671000, China

    Ning Liang & Ligang Sun

  4. Department of Colorectal Surgery, The First Affiliated Hospital of Zhejiang University, Hangzhou, 310006, China

    Chaoxu Liu

  5. State Key Laboratory of Military Stomatology and National Clinical Research Center for Oral Diseases, and Shaanxi Clinical Research Center for Oral Diseases, Department of Oral and Maxillofacial Surgery, School of Stomatology, Fourth Military Medical University, Xi’an, 710032, China

    Jing Li

  6. Department of Stomatology, Shaanxi Province People’s Hospital, Xi’an, 710068, China

    Jing Li

  7. Department of Dermatology, XiJing Hospital, Air Force Military Medical University, Xi’an, 710032, Shaanxi, China

    Yaxing Bai

  8. Anorectal Department, The First People’s Hospital of Longnan, Longnan, 742500, China

    Shuanghong Lei

  9. Department of Obstetrics and Gynecology, The 75th Group Army Hospital, Dali, Yunnan, 671000, China

    Qian Huang

  10. Department of General Surgery, Hospital of Integrated Chinese and Western Medicine, Southern Medical University, Guangzhou, 510315, China

    Liangke Tang

  11. Department of Neurology, The 74th Group Army Hospital, Guangzhou, 510318, China

    Chao Zeng

  12. Minimally Invasive tumour Comprehensive Therapy Center, Second People’s Hospital of Guangdong Province, Guangzhou, 510310, China

    Yuqun Tang

  13. Department of Pain Treatment, Tangdu Hospital, Air Force Military Medical University, Xi’an, 710038, China

    Tao Yang

  14. Department of General Surgery, Affiliated Jiangmen Hospital, Southern Medical University, Jiangmen, 529000, China

    Gang Wang

Authors
  1. Qian Wang
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  2. Ning Liang
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  3. Chaoxu Liu
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  4. Jing Li
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  5. Yaxing Bai
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  6. Shuanghong Lei
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  7. Qian Huang
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  8. Ligang Sun
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  9. Liangke Tang
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  10. Chao Zeng
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  11. Yuqun Tang
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  12. Xianli He
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  13. Tao Yang
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  14. Gang Wang
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Contributions

Conception and design: GW, XH, TY, QW. Development of methodology: JL, Y, SL. Acquisition of data (provided animals, acquired and managed patients, provided facilities, etc.): QW, QH, LS, LT. Analysis and interpretation of data (e.g., statistical analysis, biostatistics, computational analysis): QW, CL, NL. Writing, review, and/or revision of the manuscript: GW, XH, TY. Administrative, technical, or material support (i.e., reporting or organizing data, constructing databases): CZ, YT. Study supervision: GW, TY, QW, XH.

Corresponding authors

Correspondence to Qian Wang, Xianli He, Tao Yang or Gang Wang.

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Ethics approval and consent to participate

All animal experiments were approved by the Institutional Animal Care and Use Committee of Zhengzhou University in accordance with NIH guidelines.

Competing interests

The authors declare no competing interests.

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Wang, Q., Liang, N., Liu, C. et al. BEX1 supports the stemness of hepatoblastoma by facilitating Warburg effect in a PPARγ/PDK1 dependent manner. Br J Cancer (2023). https://doi.org/10.1038/s41416-023-02418-4

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  • DOI: https://doi.org/10.1038/s41416-023-02418-4

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