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 (PPARĪ³). Furthermore, pyruvate dehydrogenase kinase isozyme 1 (PDK1) is required for PPARĪ³-induced inhibition of Warburg effect in HB. In addition, BEX1 supports the stemness of HB by enhancing Warburg effect in a PPARĪ³/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 PPARĪ³/PDK1 axis. Pioglitazone could be used to target BEX1-mediated stemness properties in HB by upregulating PPARĪ³.
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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).
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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.
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Wang, Q., Liang, N., Liu, C. et al. BEX1 supports the stemness of hepatoblastoma by facilitating Warburg effect in a PPARĪ³/PDK1 dependent manner. Br J Cancer 129, 1477ā1489 (2023). https://doi.org/10.1038/s41416-023-02418-4
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DOI: https://doi.org/10.1038/s41416-023-02418-4
