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    Home > Active Ingredient News > Antitumor Therapy > J Hepatol (IF=25) Ye Qinghai/Ren Ning/Guo Lei/Li Hui/Hong Mingqi discovered a new strategy to enhance immune checkpoint therapy in hepatocellular carcinoma

    J Hepatol (IF=25) Ye Qinghai/Ren Ning/Guo Lei/Li Hui/Hong Mingqi discovered a new strategy to enhance immune checkpoint therapy in hepatocellular carcinoma

    • Last Update: 2022-03-07
    • Source: Internet
    • Author: User
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    iNature Although the advent of effective systemic therapies has revolutionized the treatment of hepatocellular carcinoma (HCC), the prognosis for patients with HCC remains dismal
    .

    Here, the study examines the pathophysiological role of PARG and evaluates the utility of targeted dePARylation in the treatment of HCC
    .

    On February 11, 2022, Ye Qinghai, Ren Ning, Guo Lei, Li Hui, and Hong Mingqi of China Medical University jointly published an online journal of Hepatology (IF=25) entitled "PARG inhibition limits HCC progression and potentiates the efficacy.
    of immune checkpoint therapy", which found that high PARG expression is closely related to poor prognosis in HCC
    .

    Hepatocyte-specific PARG deletion significantly impairs liver tumorigenesis
    .

    PARG promotes HCC growth and metastasis through DDB1-dependent regulation of c-Myc
    .

    Specifically, PARG dePARylated DDB1 and thus promoted DDB1 autoubiquitination, thereby stabilizing c-Myc protein in HCC cells
    .

    In HCC patients treated with anti-PD-1-based immunotherapy, PARG downregulation attenuated c-Myc-induced MMR expression and PARG deficiency was associated with favorable prognosis
    .

    Furthermore, PARG inhibitors can synergize with anti-PD-1 antibodies in orthotopic mouse models
    .

    In conclusion, this study finds that PARG acts as an oncogene in HCC by regulating PARG/DDB1/c-Myc signaling and can be used as a biomarker to identify HCC patients who may benefit from anti-PD-1 therapy
    .

    Our findings suggest that combined inhibition of PARG and PD-1 is an effective novel combination strategy for HCC patients
    .

    PARG is the major hydrolase involved in PARylation, acting by degrading nucleopoly (ADP-ribose) (PAR), thereby counteracting the function of PARP enzymes
    .

    Previous work has shown that PARG is involved in a variety of cellular functions, including DNA damage repair, DNA replication, chromatin regulation, transcription, mitochondrial function, and apoptosis
    .

    In recent years, accumulating evidence has also shown that abnormal PARylation catalyzed by PARG has a known tumorigenic effect, and that increased expression of PARG promotes the transformation and invasion of cancer cells
    .

    The pharmacological targeting of PARG has been shown to have promising therapeutic potential in cancer
    .

    However, the physiological role of PARG in HCC progression remains unknown, and its underlying regulatory mechanisms remain to be elucidated
    .

    In this study, the role of PARG in promoting HCC progression and metastasis was explored
    .

    Based on the LC-MS/MS analysis of PARG, DDB1 was identified as a new target of PARG
    .

    Subsequent findings suggest that PARG can act through DDB1 through its downstream oncoprotein c-MYC to drive malignant transformation and progression
    .

    Furthermore, this study found that PARG is associated with mismatch repair (MMR) protein expression, and that PARG deficiency is an indicator of MMR-deficient (dMMR) HCC
    .

    Notably, this study is the first to show that a specific inhibitor targeting PARG is synergistic with PD-1 blockade therapy in a preclinical model of HCC
    .

    In conclusion, this study found that PARG acts as an oncogene in HCC by regulating PARG/DDB1/c-Myc signaling and can be used as a biomarker to identify HCC patients who may benefit from anti-PD-1 therapy
    .

    Our findings suggest that combined inhibition of PARG and PD-1 is an effective novel combination strategy for HCC patients
    .

    Reference message: https://#%20
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