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

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.

RNA sequence analysis reveals pathways and candidate genes associated with liver injury in a rat pancreatitis model.

BACKGROUND: The morbidity and mortality associated with acute pancreatitis (AP) are largely attributable to abnormalities that occur in distant organs, such as liver and lungs. Pancreatitis-associated liver injury (PALI) remains a serious and even fatal complication during the progression of AP. However, the exact pathophysiological mechanism is still unclear. METHODS: In the present study, we used, for the first time, RNA-seq method to reveal pathways and candidate genes associated with PALI in rats. AP was induced by retrograde injection of sodium taurocholate (5%) into the biliopancreatic duct. The RNA-seq results of selected genes were validated by RT-PCR and immunohistochemistry assay. RESULTS: GO (Gene Ontology) and KEGG (Kyoto Encyclopedia of Genes and Genomes) pathway analysis indicated that Toll like receptor 4 (TLR4) signaling pathway and transforming growth factor ß1 (TGF-ß1) and p38 mitogen-activated protein kinase (MAPK) signaling pathway (TGF-ß1-p38 MAPK) were involved in the course of PALI. In addition, other factors were also found to be involved in the course of PALI, such as the decreased antioxidant activity, excessive production of inflammatory mediators and alterations in liver metabolism. CONCLUSIONS: The study sheds some new insight on our understanding of the pathophysiology of PALI and provides some clues to the identification of potential therapeutic targets.