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Original research
USP22 promotes hypoxia-induced hepatocellular carcinoma stemness by a HIF1α/USP22 positive feedback loop upon TP53 inactivation
  1. Sunbin Ling1,2,
  2. Qiaonan Shan1,2,
  3. Qifan Zhan1,2,
  4. Qianwei Ye1,2,
  5. Peng Liu1,2,
  6. Shengjun Xu1,2,
  7. Xin He3,
  8. Jian Ma3,
  9. Jiajia Xiang4,
  10. Guangjiang Jiang1,2,
  11. Xue Wen5,
  12. Zijie Feng3,
  13. Yuan Wu3,
  14. Tingting Feng1,2,6,
  15. Li Xu1,2,
  16. Kangchen Chen1,2,
  17. Xuanyu Zhang1,2,
  18. Rongli Wei1,2,
  19. Chenzhi Zhang1,2,
  20. Beini Cen2,
  21. Haiyang Xie2,
  22. Penghong Song2,
  23. Jimin Liu7,
  24. Shusen Zheng1,2,
  25. Xiao Xu1,2
  1. 1 Department of Hepatobiliary and Pancreatic Surgery, the First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310003, China
  2. 2 NHC Key Laboratory of Combined Multi-organ Transplantation; Key Laboratory of the Diagnosis and Treatment of Organ Transplantation, CAMS, Hangzhou, Zhejiang 310003, China
  3. 3 Department of Cancer Biology, Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, 421 Curie Blvd, Philadelphia, PA 19014, Pennsylvania, USA
  4. 4 Center for Bionanoengineering and Key Laboratory of Biomass Chemical Engineering of Ministry of Education, College of Chemical and Biological Engineering, Zhejiang University, Hangzhou, Zhejiang 310027, China
  5. 5 Department of Pathology, the First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310003, China
  6. 6 Department of Abdominal Medical Oncology, Zhejiang Cancer Hospital, Hangzhou, Zhejiang 310022, China
  7. 7 Department of Pathology and Molecular Medicine, Faculty of Health Sciences, McMaster University, Hamilton, Ontario L8J 0B4, Canada
  1. Correspondence to Professor Xiao Xu, Department of Hepatobiliary and Pancreatic Surgery, the First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310003, China; zjxu{at}


Objective We aimed to elucidate the mutual regulation mechanism of ubiquitin-specific protease 22 (USP22) and hypoxia inducible factor-1α (HIF1α), and the mechanism they promote the stemness of hepatocellular carcinoma (HCC) cells under hypoxic conditions.

Design Cell counting, migration, self-renewal ability, chemoresistance and expression of stemness genes were established to detect the stemness of HCC cells. Immunoprecipitation, ubiquitination assay and chromatin immunoprecipitation assay were used to elucidate the mutual regulation mechanism of USP22 and HIF1α. HCC patient samples and The Cancer Genome Atlas data were used to demonstrate the clinical significance. In vivo USP22-targeting experiment was performed in mice bearing HCC.

Results USP22 promotes hypoxia-induced HCC stemness and glycolysis by deubiquitinating and stabilising HIF1α. As direct target genes of HIF1α, USP22 and TP53 can be transcriptionally upregulated by HIF1α under hypoxic conditions. In TP53 wild-type HCC cells, HIF1α induced TP53-mediated inhibition of HIF1α-induced USP22 upregulation. In TP53-mutant HCC cells, USP22 and HIF1α formed a positive feedback loop and promote the stemness of HCC. HCC patients with a loss-of-function mutation at TP53 and high USP22 and/or HIF1α expression tend to have a worse prognosis. The USP22-targeting lipopolyplexes caused high tumour inhibition and high sorafenib sensitivity in mice bearing HCC.

Conclusion USP22 promotes hypoxia-induced HCC stemness by a HIF1α/USP22 positive feedback loop on TP53 inactivation. USP22 is a promising target for the HCC therapy.

  • USP22
  • HIF1α
  • hepatocellular carcinoma
  • cancer stemness
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  • SL, QS and QZ contributed equally.

  • Contributors XX, SL, QS, SZ, HX and PS designed the research. SL, QS, QZ, QY, PL, SX, JX, XW, TF, LX, KC, BC, GJ and XZ performed experiments and acquisition of data. SL, QS, QZ, XH, JM, ZF, YW and JL analyzed and interpreted data. SL, QS, QZ. QY, RW, CZ and XX wrote the paper and critically reviewed the manuscript. All authors read and approved the final version of the manuscript.

  • Funding This work was supported in part by funding from the National Science and Technology Major Project of China (2017ZX10203205), the National Natural Science Funds for Distinguished Young Scholar of China (81625003) and the Cheung Kong Scholars Program of China to XX, the National Natural Science Foundation of China (81902407) to SL; the Zhejiang Science and Technology Key Research and Development Project (2018C04010) to SL; the Zhejiang Public Welfare Technology Research Program (LGF18H160015) to TF.

  • Competing interests None declared.

  • Patient consent for publication Not required.

  • Ethics approval The Medical Ethics Committee of the First Affiliated Hospital of Zhejiang University.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Data availability statement Data are available in a public, open access repository.

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