Ubiquitin-specific protease 7 accelerates p14(ARF) degradation by deubiquitinating thyroid hormone receptor-interacting protein 12 and promotes hepatocellular carcinoma progression

Hepatology. 2015 May;61(5):1603-14. doi: 10.1002/hep.27682. Epub 2015 Feb 13.


The prognosis for hepatocellular carcinoma (HCC) remains dismal in terms of overall survival (OS), and its molecular pathogenesis has not been completely defined. Here, we report that expression of deubiquitylase ubiquitin-specific protease 7 (USP7) is higher in human HCC tissues than in matched peritumoral tissues. Ectopic USP7 expression promotes growth of HCC cells in vivo and in vitro. Mechanistically, USP7 overexpression fosters HCC cell growth by forming a complex with and stabilizing thyroid hormone receptor-interacting protein 12 (TRIP12), which induces constitutive p14(ARF) ubiquitination. Clinically, USP7 overexpression is significantly correlated with a malignant phenotype, including larger tumor size, multiple tumor, poor differentiation, elevated alpha-fetoprotein, and microvascular invasion. Moreover, overexpression of USP7 and/or TRIP12 correlates with shorter OS and higher cumulative recurrence rates of HCC.

Conclusion: USP7 stabilizes TRIP12 by deubiquitination, thus constitutively inactivating p14(ARF) and promoting HCC progression. This represents a novel marker for predicting prognosis and a potential therapeutic target for HCC.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Carcinoma, Hepatocellular / metabolism*
  • Carrier Proteins / metabolism*
  • Disease Progression
  • Female
  • Humans
  • Liver Neoplasms / metabolism*
  • Male
  • Middle Aged
  • Prognosis
  • Tumor Suppressor Protein p14ARF / metabolism*
  • Ubiquitin Thiolesterase / physiology*
  • Ubiquitin-Protein Ligases / metabolism*
  • Ubiquitin-Specific Peptidase 7


  • Carrier Proteins
  • Tumor Suppressor Protein p14ARF
  • TRIP12 protein, human
  • Ubiquitin-Protein Ligases
  • USP7 protein, human
  • Ubiquitin Thiolesterase
  • Ubiquitin-Specific Peptidase 7