Ectosomal HK1 Generated In Liver Fibrosis Promotes HCC Development Through Glycolysis

The relationship between tumor and tumor microenvironment(TME)was described as "seed and soil".Most of cancer hallmarks are enabled or sustained with the support of TME.In the clinical,hepatocellular carcinoma(HCC)development is usually associated with hepatic fibrosis.Recent evidences suggest that extracellular vesicles play crucial roles in tumor development.However,whether the fibrotic microenvironment promote HCC development through extracellular vesicles remains elusive.Hexokinase 1(HK1),the first enzymes committed to glycolysis,is essential for glucose utilization.Here,we revealed that HCC cells hijacked ectosomal HK1 derived from fibrotic hepatic stellate cells(HSCs),which promotes HCC cells proliferation through reprogramming glycolysis pathway.This finding was further verified in vivo by different mouse models,including orthotopic xenograft tumor model and DEN/CCl4-induced primary tumor.Mechanistically,TGF-β could repress the expression of depalmitoylation enzyme ABHD17B,resulting in higher level of HK1 palmitoylation.Palmitoylated HK1 was translocated from the mitochondria to the plasma membrane and then excretion through mediation of TSG101 that is important for direct plasma membrane budding to form ectosomes.Once released,ectosomal HK1 was hijacked into HCC cells,which promotes HCC cell proliferation through reprogramming glycolysis pathway.In sum,this study not only demonstrates that fibrotic TME promotes HCC development by the way of vicious ectosomal HK1 excretion,but also reveals that HCC development can be delayed by blocking the delivery of ectosomal HK1 from HSCs to HCC cells.This study might provide a new target for HCC treatment in clinical.