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    Home > Active Ingredient News > Digestive System Information > Nature subjournal: Revealed a new mechanism of hepatic stellate cell exocryo-hexokinase HK1 to accelerate the progression of liver cancer

    Nature subjournal: Revealed a new mechanism of hepatic stellate cell exocryo-hexokinase HK1 to accelerate the progression of liver cancer

    • Last Update: 2022-10-21
    • Source: Internet
    • Author: User
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    On October 3, 2022, the research group of Wu Qiao's research group of the School of Life Sciences of Xiamen University published a publication in the journal Nature Metabolism entitled : HK1 from hepatic stellate cell-derived extracellular vesicles promotes progression of hepatocellular carcinoma
    .

    The study elucidated TGF-β-induced hepatic stellate cells (HSCs) during liver fibrosis The palmitoylation modification of hexokinase HK1 promotes the exosomement of HK1 through extracellular vesicles, while hepatoma cells hijack extracellular vesicles HK1 derived from fibrotic HSCs to enhance their own glycolytic ability and promote the proliferation of hepatoma cells.
    In addition, it was found that the small molecule compound PDNPA blocks TGF-β-induced HK1 exosomes by targeting the nuclear receptor Nur77, thereby inhibiting the progression of liver cancer, revealing the new function
    of PDNPA inhibition of HK1 exosomes.


    The research team extracted HSCs in resting and activated states extracellular vesicles, and analyzed them by protein quantitative mass spectrometry to look for potential cancer-promoting proteins
    in the vesicles.
    By comparing and analyzing the changes of exoprotein profiles before and after HSCs activation, it was found that hexokinase HK1, a protein associated with metabolic pathways, was one of
    the most obvious proteins after HSCs activation.
    Further studies found that in the process of liver fibrosis, the profibrotic cytokine TGF-β promoted its transport from mitochondria to the cytoplasmic membrane by inducing palmitoylation of HK1, and was sorted into lEVs
    (large EVs) and then exosomed
    in a TSG101-dependent manner.
    The process of HK1 palmitoylation is closely related
    to TGF-β down-regulation of the expression of depalmitoylase ABHD17B.

    By analyzing the single-cell data of clinical liver cancer and the CCLE database, the researchers found that hepatoma cells had low or no expression of HK1
    .
    However, hepatoma cells increase their own HK1 levels by hijacking the lEV HK1 secreted by HSCs, thereby increasing the glycolysis level in hepatoma cells to promote tumor proliferation
    .
    The researchers further verified that HSCs-derived lEV HK1 promoted liver cancer progression
    in mice through a series of mouse models, including liver in situ transplant tumor model, liver cancer cell lung metastasis model, and DEN/CCl4- or HFD/STZ-induced primary liver cancer model.

    The nuclear receptor Nur77 has been reported to inhibit TGF-β-induced fibrotic processes
    .
    In this study, the researchers further found that Nur77 can transcribe and activate the expression level of ABHD17B gene, thereby inhibiting palmitoylation modification and exocryology
    of HK1.
    However, during the fibrosis process, TGF-β induces protein kinase Akt phosphorylation of Nur77 in HSCs, resulting in its degradation, thereby losing the ability to regulate the
    expression of depalmitoylase ABHD17B.

    Based on this, blocking the binding of Nur77 and Akt may avoid the degradation of Nur77 and ensure that Nur77 inhibits HK1 exosomes
    through ABHD17B.
    Through screening, the researchers found that the small molecule compound PDNPA can bind to the Nur77 ligand binding domain from the laboratory-constructed library of targeted Nur77 compounds, thereby forming a spatial barrier to block the binding of Akt to the Nur77 ligand binding domain, thereby greatly increasing the expression level of Nur77 and inhibiting the exocry
    of HK1 during fibrosis.
    Transgenic mice specifically knocked out Nur77 within HSCs further validated a new pathway
    for the compound PDNPA to inhibit the development and progression of liver cancer by targeting Nur77.

    In summary, this study elucidated a novel mechanism of unreported liver fibrosis promoting liver cancer progression, and screened the potential small molecule compound PDNPA to inhibit liver cancer process
    by blocking HK1 exosomes in HSCs.


    Metabolic reprogramming is one of the important features of tumors, tumor cells remodel their own metabolism to meet the material and energy requirements
    of rapid proliferation.
    HKs family proteins were found to be differentially expressed
    in hepatocytes and hepatoma cells.
    HCCs typically express the HK2 subtype with high affinity for glucose and are considered potential therapeutic targets
    for HCC.
    The HK1 subtype 4, which has the highest glucose affinity, is almost not transcribed in hepatoma cells, and its function has been neglected
    in liver cancer for a long time.
    The study found that hepatoma cells can hijack the HL1 of HSCs, which can not only enhance the glycolytic level of tumor cells, but also ensure the utilization of glucose by tumor cells under low glucose concentration conditions, so as to adapt to the insufficient
    nutrition in tumor tissues during the development of liver cancer.
    Although HK2 is considered to be an ideal target for the treatment of HK1-HK2+ tumor types, this study suggests that combining extracellular vesicle HK1 that targets the tumor's own HK2 and HSCs-derived sources will be a more ideal treatment strategy
    for liver cancer.

    Malignant proliferating liver cancer cells like ancient marching teams (left) require a large supply
    of supplies.
    Activated hepatic stellate cells act as logistics transporters (right) to provide material support
    for liver cancer cells.
    The compound PDNPA can block the delivery of hepatic stellate cells to hepatocellular cancer cells and inhibit the progression of liver cancer (top right).


    Links to papers: style="display: none;">

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