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Hepatocyte phosphatase DUSP22 mitigates NASH-HCC progression by targeting FAK

Author

Listed:
  • Chenxu Ge

    (Chongqing University of Education
    Chongqing University
    Chongqing University of Education)

  • Jun Tan

    (Chongqing University of Education
    Chongqing University of Education)

  • Xianling Dai

    (Chongqing University of Education
    Chongqing University)

  • Qin Kuang

    (Chongqing University of Education
    Chongqing University)

  • Shaoyu Zhong

    (Chongqing University of Education
    Chongqing University of Education)

  • Lili Lai

    (Chongqing University of Education
    Chongqing University of Education)

  • Chao Yi

    (Chongqing University of Education
    Chongqing University of Education)

  • Yan Sun

    (Chongqing University of Education
    Chongqing University)

  • Jing Luo

    (Chongqing University of Education)

  • Chufeng Zhang

    (Shandong First Medical University & Shandong Academy of Medical Sciences)

  • Liancai Zhu

    (Chongqing University)

  • Bochu Wang

    (Chongqing University)

  • Minxuan Xu

    (Chongqing University of Education
    Chongqing University
    Chongqing University of Education)

Abstract

Nonalcoholic steatohepatitis (NASH), a common clinical disease, is becoming a leading cause of hepatocellular carcinoma (HCC). Dual specificity phosphatase 22 (DUSP22, also known as JKAP or JSP-1) expressed in numerous tissues plays essential biological functions in immune responses and tumor growth. However, the effects of DUSP22 on NASH still remain unknown. Here, we find a significant decrease of DUSP22 expression in human and murine fatty liver, which is mediated by reactive oxygen species (ROS) generation. Hepatic-specific DUSP22 deletion particularly exacerbates lipid deposition, inflammatory response and fibrosis in liver, facilitating NASH and non-alcoholic fatty liver disease (NAFLD)-associated HCC progression. In contrast, transgenic over-expression, lentivirus or adeno-associated virus (AAV)-mediated DUSP22 gene therapy substantially inhibit NASH-related phenotypes and HCC development in mice. We provide mechanistic evidence that DUSP22 directly interacts with focal adhesion kinase (FAK) and restrains its phosphorylation at Tyr397 (Y397) and Y576 + Y577 residues, subsequently prohibiting downstream activation of extracellular signal-regulated kinase 1/2 (ERK1/2) and nuclear factor-κB (NF-κB) cascades. The binding of DUSP22 to FAK and the dephosphorylation of FAK are indispensable for DUSP22-meliorated NASH progression. Collectively, our findings identify DUSP22 as a key suppressor of NASH-HCC, and underscore the DUSP22-FAK axis as a promising therapeutic target for treatment of the disease.

Suggested Citation

  • Chenxu Ge & Jun Tan & Xianling Dai & Qin Kuang & Shaoyu Zhong & Lili Lai & Chao Yi & Yan Sun & Jing Luo & Chufeng Zhang & Liancai Zhu & Bochu Wang & Minxuan Xu, 2022. "Hepatocyte phosphatase DUSP22 mitigates NASH-HCC progression by targeting FAK," Nature Communications, Nature, vol. 13(1), pages 1-21, December.
  • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-33493-5
    DOI: 10.1038/s41467-022-33493-5
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    References listed on IDEAS

    as
    1. Minxuan Xu & Jun Tan & Wei Dong & Benkui Zou & Xuepeng Teng & Liancai Zhu & Chenxu Ge & Xianling Dai & Qin Kuang & Shaoyu Zhong & Lili Lai & Chao Yi & Tingting Tang & Junjie Zhao & Longyan Wang & Jin , 2022. "The E3 ubiquitin-protein ligase Trim31 alleviates non-alcoholic fatty liver disease by targeting Rhbdf2 in mouse hepatocytes," Nature Communications, Nature, vol. 13(1), pages 1-20, December.
    2. Ju-Pi Li & Chia-Yu Yang & Huai-Chia Chuang & Joung-Liang Lan & Der-Yuan Chen & Yi-Ming Chen & Xiaohong Wang & Alice J. Chen & John W. Belmont & Tse-Hua Tan, 2014. "The phosphatase JKAP/DUSP22 inhibits T-cell receptor signalling and autoimmunity by inactivating Lck," Nature Communications, Nature, vol. 5(1), pages 1-13, May.
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    Cited by:

    1. Qilun Zhang & Xuting Shen & Xin Yuan & Jing Huang & Yaling Zhu & Tengteng Zhu & Tao Zhang & Haibo Wu & Qian Wu & Yinguang Fan & Jing Ni & Leilei Meng & Anyuan He & Chaowei Shi & Hao Li & Qingsong Hu &, 2024. "Lipopolysaccharide binding protein resists hepatic oxidative stress by regulating lipid droplet homeostasis," Nature Communications, Nature, vol. 15(1), pages 1-17, December.

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