Human Gene Set: FEKIR_HEPARG_SPHERE_VS_HEPARG_DN


Standard name FEKIR_HEPARG_SPHERE_VS_HEPARG_DN
Systematic name M48359
Brief description Genes down-regulated in the cancer stem HepaRG-sphere vs HepaRG at 10 days of differentiation
Full description or abstract Human hepatocellular carcinoma (HCC) heterogeneity promotes recurrence and therapeutic resistance. We recently have demonstrated that inflammation favors hepatocyte retrodifferentiation into progenitor cells. Here, we identified molecular effectors inducing HCC metabolic reprogramming, chemoresistance and invasiveness of retrodifferentiated stem cells. Spheroid cultures of human HepaRG-progenitors (HepaRG-Spheres), HBG-BC2, HepG2 and HuH7 cells and isolation of side population (SP) from HepaRG cells (HepaRG-SP) were followed by transcriptomics, signaling pathway analysis and evaluation of chemotherapies. Gene expression profiles of HepaRG-SP and HepaRG-Spheres were enriched in signatures related to cancer stem cells, metastasis and recurrence and showed that HepaRG-progenitors can further retrodifferentiate into a more immature state. The transcriptome from these stem cells matched that of proliferative bad outcome HCCs in a cohort of 457 patients. These HCC stem cells highly expressed cytokines triggering retrodifferentiation and displayed high migration/invasion potential. Importantly, they showed changes in mitochondrial activity with reduced membrane potential, low ATP production and high lactate production. These changes were in part related to angiopoietin-like 4 (ANGPTL4)-induced upregulation of pyruvate dehydrogenase kinase 4 (PDK4), an inhibitor of mitochondrial pyruvate dehydrogenase. Interestingly, up-regulation of ANGPTL4 and PDK4 paralleled that of stem cells markers in human HCC specimens. Moreover, the PDK4 inhibitor dichloroacetate reversed chemoresistance to sorafenib or cisplatin in HCC stem cells derived from four HCC cell lines. In conclusion, retrodifferentiated cancer cells develop enhanced invasion and therapeutic resistance through ANGPTL4 and PDK4. Restoration of mitochondrial activity in combination with chemotherapy represents an attractive therapeutic approach in HCCs.
Collection C2: Curated
      CGP: Chemical and Genetic Perturbations
Source publication Pubmed 30837223   Authors: Fekir K,Dubois-Pot-Schneider H,Désert R,Daniel Y,Glaise D,Rauch C,Morel F,Fromenty B,Musso O,Cabillic F,Corlu A
Exact source Supplemental Table 3 in Fekir et al., Cancer Research (2019), 79: 1869-1883
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Source species Homo sapiens
Contributed by Anne Corlu (INSERM (Institut National de la Santé et de la Recherche Mtédicale), France.)
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identifier namespace		 Human_Ensembl_Gene_ID
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