2. Academic Validation
  3. Constitutive photomorphogenic protein 1 ubiquitinates interleukin-1 receptor accessory protein in human liver cancer

Constitutive photomorphogenic protein 1 ubiquitinates interleukin-1 receptor accessory protein in human liver cancer

  • J Cancer Res Clin Oncol. 2023 Sep 12. doi: 10.1007/s00432-023-05367-w.
Kuan Cao # 1 2 3,  Zhiyi Liu # 1 2 3,  Jin Liu # 1 2 3 4,  Qinghe Hu 1 2 3,  Wengang Shan 1 2 3,  Bin Hu 1 2 3,  Hengliang Shi 5 6 7 8,  Bin Zhang 9 10
Affiliations

Affiliations

  • 1 Institute of Digestive Diseases, Xuzhou Medical University, No. 84 West Huaihai Road, Xuzhou, 221002, Jiangsu, China.
  • 2 Research Center of Digestive Diseases, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu, China.
  • 3 Department of General Surgery, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu, China.
  • 4 Hepatobiliary Pancreatic Surgery, The Second Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu, China.
  • 5 Institute of Digestive Diseases, Xuzhou Medical University, No. 84 West Huaihai Road, Xuzhou, 221002, Jiangsu, China. shl@xzhmu.edu.cn.
  • 6 Research Center of Digestive Diseases, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu, China. shl@xzhmu.edu.cn.
  • 7 Department of General Surgery, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu, China. shl@xzhmu.edu.cn.
  • 8 Central Laboratory, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu, China. shl@xzhmu.edu.cn.
  • 9 Research Center of Digestive Diseases, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu, China. zhangbin@xzhmu.edu.cn.
  • 10 Department of General Surgery, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu, China. zhangbin@xzhmu.edu.cn.
  • # Contributed equally.
PMID: 37700160 DOI: 10.1007/s00432-023-05367-w
Abstract

Background: Constitutive photomorphogenic protein 1 (COP1) plays a pivotal role in the development and progression of several human cancers and is reported to be upregulated in liver Cancer. However, the role of COP1 in human liver Cancer is unclear.

Methods: We analyzed the COP1 expression in normal liver and liver Cancer tissue samples using western blot and immunohistochemical analysis. We overexpressed and silenced COP1 in HepG2 and Huh7 cells and analyzed the effect on liver Cancer cell proliferation. Additionally, COP1 was used as a bait to screen COP1-interacting proteins in a human cDNA library in a yeast two-hybrid screen and the results were confirmed with co-immunoprecipitation (co-IP) assays. Moreover, immunofluorescence staining was performed to assess co-localization. The protein levels of COP1 and mIL1RAcP were determined in clinical samples.

Results: COP1 was upregulated in liver Cancer samples compared to that in normal tissue samples. COP1 overexpression promoted proliferation of liver Cancer cells, while COP1 knockdown exerted the opposite effect. Yeast two-hybrid screen identified interleukin-1 receptor accessory protein (IL1RAP) as a potential COP1-interacting protein. Co-IP assays further confirmed that COP1 interacts with both preIL1RAP and membrane-bound form of IL1RAP (mIL1RAP). Furthermore, COP1 upregulated mIL1RAP protein levels and promoted nuclear translocation and activation of the nuclear factor kappa B (NF-κB) (p50/p65) dimer. Additionally, we demonstrated that COP1 regulated mIL1RAP expression through K63-linked polyubiquitination, suggesting that COP1 plays a role in stabilizing mIL1RAP. Finally, the protein levels of COP1 and mIL1RAcP were found to be positively correlated in clinical samples.

Conclusion: COP1 regulates IL1RAP, which in turn results in activation of the NF-κB signaling. Our findings suggest that the COP1/IL1RAP/NF-κB axis promotes proliferation of liver Cancer cells and is a potential target for the treatment of liver Cancer.

Keywords

IL1RAcP; Liver cancer; NF-κB; Polyubiquitination.

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