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

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机构: [1]Department of General Surgery, Tangdu Hospital, Air Force Military Medical University, Xi'an, 710032, China. [2]Department of General Surgery, The First Affiliated Hospital, Zhengzhou University, Zhengzhou, 450052, China. [3]Department of General Surgery, The 75th Group Army Hospital, Dali, 671000, China. [4]Department of Colorectal Surgery, The First Affiliated Hospital of Zhejiang University, Hangzhou, 310006, China. [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. [6]Department of Stomatology, Shaanxi Province People's Hospital, Xi'an, 710068, China. [7]Department of Dermatology, XiJing Hospital, Air Force Military Medical University, Xi'an, 710032, Shaanxi, China. [8]Anorectal Department, The First People's Hospital of Longnan, Longnan, 742500, China. [9]Department of Obstetrics and Gynecology, The 75th Group Army Hospital, Dali, Yunnan, 671000, China. [10]Department of General Surgery, Hospital of Integrated Chinese and Western Medicine, Southern Medical University, Guangzhou, 510315, China. [11]Department of Neurology, The 74th Group Army Hospital, Guangzhou, 510318, China. [12]Minimally Invasive tumour Comprehensive Therapy Center, Second People's Hospital of Guangdong Province, Guangzhou, 510310, China. [13]Department of General Surgery, Tangdu Hospital, Air Force Military Medical University, Xi'an, 710032, China. [14]Department of Pain Treatment, Tangdu Hospital, Air Force Military Medical University, Xi'an, 710038, China. [15]Department of General Surgery, Tangdu Hospital, Air Force Military Medical University, Xi'an, 710032, China. [16]Department of General Surgery, Affiliated Jiangmen Hospital, Southern Medical University, Jiangmen, 529000, China.
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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.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.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.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.© 2023. The Author(s), under exclusive licence to Springer Nature Limited.

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大类 | 1 区 医学
小类 | 2 区 肿瘤学
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大类 | 2 区 医学
小类 | 2 区 肿瘤学
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Q1 ONCOLOGY
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Q1 ONCOLOGY

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第一作者机构: [1]Department of General Surgery, Tangdu Hospital, Air Force Military Medical University, Xi'an, 710032, China. [2]Department of General Surgery, The First Affiliated Hospital, Zhengzhou University, Zhengzhou, 450052, China.
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通讯机构: [1]Department of General Surgery, Tangdu Hospital, Air Force Military Medical University, Xi'an, 710032, China. [2]Department of General Surgery, The First Affiliated Hospital, Zhengzhou University, Zhengzhou, 450052, China. [15]Department of General Surgery, Tangdu Hospital, Air Force Military Medical University, Xi'an, 710032, China. [16]Department of General Surgery, Affiliated Jiangmen Hospital, Southern Medical University, Jiangmen, 529000, China.
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