4.6 Article

Knockout of ASPP2 promotes DEN-induced hepatocarcinogenesis via the NF-κB pathway in mice

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CANCER GENE THERAPY
卷 29, 期 2, 页码 202-214

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SPRINGERNATURE
DOI: 10.1038/s41417-021-00300-0

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资金

  1. Beijing Natural Science Foundation [7192084]
  2. National Science and Technology Major Special Program of the 13th Five-Year Plan for the Prevention and Control of Major Infectious Diseases [2018ZX10302205-005]
  3. National Natural Science Foundation of China [81672026, 81870424]
  4. Beijing Nature Science Foundation Program and Scientific Research Key Program of Beijing Municipal Commission of Education [KZ201810025037]

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ASPP2 protein plays an important role in hepatitis and hepatocellular carcinoma, and the absence of ASPP2 can activate the NF-kappa B pathway to promote hepatocarcinogenesis.
Apoptosis-stimulating protein p53 2 (ASPP2) is a member of the p53-binding protein family, which is closely related to tumor development. However, the precise mechanism of ASPP2 in liver inflammation and tumorigenesis remains largely unclear. We aimed to characterize the mechanistic significance and clinical implication of ASPP2 in hepatitis and hepatocellular carcinoma (HCC). In this study, ASPP2 knockout (APKO) mice were generated to confirm the role of ASPP2 in the development of hepatitis and HCC. Liver tissues from mice were analyzed by immunohistochemistry, Western blotting, proteomic analysis, ChIP-Seq, and qRT-PCR to evaluate the role of ASPP2 in DEN-induced hepatitis and HCC. We found that APKO promoted the formation of hepatitis/hepatocarcinoma and the increased expression of proinflammatory factors. The proteomics and Western blotting results showed that APKO activated the NF-kappa B signaling pathway. Further, ChIP-Seq results revealed that NF-kappa B target genes were dramatically increased in APKO mice. In contrast, blockade of the NF-kappa B pathway by QNZ reduced the expression of proinflammatory factors and the susceptibility of APKO mice to DEN-induced hepatocarcinogenesis. These results suggested that the absence of ASPP2 activates the NF-kappa B pathway to promote the occurrence of DEN-induced hepatocarcinogenesis, indicating that ASPP2 may be a potential target for the treatment of hepatocarcinoma.

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