Cell Biochemistry and Biophysics

, Volume 61, Issue 3, pp 703–710 | Cite as

The Co-expression of USP22 and BMI-1 May Promote Cancer Progression and Predict Therapy Failure in Gastric Carcinoma

  • Dong-Dong Yang
  • Bin-Bin Cui
  • Ling-yu Sun
  • Hong-qun Zheng
  • Qi Huang
  • Jin-Xue Tong
  • Qi-Fan ZhangEmail author
Translational Biomedical Research


Recent experimental evidence support the model in which the simultaneous induction of BMI-1 and USP22 is critical during cancer progression. Whether this model may affect gastric cancer (GC) progression is worthy of additional study. In this study, we examined the significance of the USP22 and BMI-1 expression in GC (n = 219), non-cancerous mucosa (n = 37), and lymph node metastasis (n = 37). The protein expression level of USP22 and BMI-1 were concomitantly up-regulated from non-cancerous mucosa to primary carcinoma and from carcinomas to lymph node metastasis (P < 0.001). A statistical correlation was observed between USP22 and BMI-1 expression in GC tissues (n = 219, r = 0.634, P < 0.001) and in lymph node metastasis (n = 37, r = 0.689, P < 0.001). The incidence of positive expression was 57.08% for USP22, 49.32% for BMI-1, and 45.21% for USP22/BMI-1 in 219 GC tissues, respectively. Co-positive of USP22/BMI-1 was significantly correlated with gross features (x 2 = 14.256, P < 0.001), differentiation (x 2 = 5.872, P = 0.015), pT classification (x 2 = 18.486, P < 0.001), pN classification (x 2 = 9.604, P = 0.002), pM classification (x 2 = 32.766, P < 0.001), and AJCC stage (x 2 = 58.278, P < 0.001). Notably, high USP22/BMI-1 expression was significantly associated with shorter disease-specific survival (P < 0.001). By Cox regression analysis, co-positive of USP22/BMI-1 was found to be an independent prognostic factor (P = 0.002). Our results indicated the simultaneous activation of USP22 and BMI-1 may associate with GC progression and therapy failure.


USP22 BMI-1 Cancer progression Gastric carcinoma 



This work was supported by Natural Science Foundation of Heilongjiang Province (ZD200920). This work was also supported by grant of Harbin Science and Technology Bureau (2007AA3CS083).


  1. 1.
    Glinsky, G. V. (2005). Death-from-cancer signatures and contribution of stem cells to metastatic cancer. Cell Cycle, 4, 1171–1175.PubMedCrossRefGoogle Scholar
  2. 2.
    Glinsky, G. V., Berezovska, O., & Glinskii, A. B. (2005). Microarray analysis identifies a death from cancer signature predicting therapy failure in patients with multiple types of cancer. Journal of Clinical Investigation, 115, 1503–1521.PubMedCrossRefGoogle Scholar
  3. 3.
    Glinsky, G. V. (2006). Integration of HapMap-based SNP pattern analysis and gene expression profiling reveals common SNP profiles for cancer therapy outcome predictor genes. Cell Cycle, 5, 2613–2625.PubMedCrossRefGoogle Scholar
  4. 4.
    Glinsky, G. V. (2008). “Stemness” genomics law governs clinical behavior of human cancer: implications for decision making in disease management. Journal of Clinical Oncology, 26, 2846–2853.PubMedCrossRefGoogle Scholar
  5. 5.
    Glinsky, G. V. (2006). Genomic models of metastatic cancer: functional analysis of death-from-cancer signature genes reveals aneuploid, anoikis-resistant, metastasis-enabling phenotype with altered cell cycle control and activated Polycomb Group (PcG) protein chromatin silencing pathway. Cell Cycle, 5, 1208–1216.PubMedCrossRefGoogle Scholar
  6. 6.
    Liu, S., Dontu, G., Mantle, I. D., Patel, S., Ahn, N. S., Jackson, K. W., et al. (2006). Hedgehog signaling and bmi-1 regulate self-renewal of normal and malignant human mammary stem cell. Cancer Research, 66, 6063–6071.PubMedCrossRefGoogle Scholar
  7. 7.
    Park, I. K., Qian, D., Kiel, M., Becker, M. W., Pihalja, M., Weissman, I. L., et al. (2003). Bmi-1 is required for maintenance of adult self-renewing haematopoietic stem cells. Nature, 423, 302–305.PubMedCrossRefGoogle Scholar
  8. 8.
    Molofsky, A. V., Pardal, R., Iwashita, T., Park, I. K., Clarke, M. F., & Morrison, S. J. (2003). Bmi-1 dependence distinguishes neural stem cell self-renewal from progenitor proliferation. Nature, 425, 962–967.PubMedCrossRefGoogle Scholar
  9. 9.
    Lessard, J., & Sauvageau, G. (2003). Bmi-1 determines the proliferative capacity of normal and leukaemic stem cells. Nature, 423, 255–260.PubMedCrossRefGoogle Scholar
  10. 10.
    Berezovska, O. P. (2006). Essential role for activation of the Polycomb group (PcG) protein chromatin silencing pathway in metastatic prostate cancer. Cell Cycle, 5, 1886–1901.PubMedCrossRefGoogle Scholar
  11. 11.
    Lee, H. J., Kim, M. S., Shin, J. M., Park, T. J., Chung, H. M., & Baek, K. H. (2006). The expression patterns of deubiquitinating enzymes, USP22 and Usp22. Gene Expression Patterns, 6, 277–284.PubMedCrossRefGoogle Scholar
  12. 12.
    Zhang, X. Y., Pfeiffer, H. K., Thorne, A. W., & McMahon, S. B. (2008). USP22, an hSAGA subunit and potential cancer stem cell marker, reverses the polycomb-catalyzed ubiquitylation of histone H2A. Cell Cycle, 7, 1522–1524.PubMedCrossRefGoogle Scholar
  13. 13.
    Zhang, X. Y., Varthi, M., Sykes, S. M., Phillips, C., Warzecha, C., Zhu, W., et al. (2008). The putative cancer stem cell marker USP22 is a subunit of the human SAGA complex required for activated transcription and cell-cycle progression. Molecular Cell, 29, 102–111.PubMedCrossRefGoogle Scholar
  14. 14.
    Zhao, Y., Lang, G., Ito, S., Bonnet, J., Metzger, E., Sawatsubashi, S., et al. (2008). A TFTC/STAGA module mediates histone H2A and H2B deubiquitination, coactivates nuclear receptors, and counteracts heterochromatin silencing. Molecular Cell, 29, 92–101.PubMedCrossRefGoogle Scholar
  15. 15.
    Pijnappel, W. W., & Timmers, H. T. (2008). Dubbing SAGA unveils new epigenetic crosstalk. Molecular Cell, 29, 152–154.PubMedCrossRefGoogle Scholar
  16. 16.
    Yu, Q., Su, B., Liu, D., Liu, B., Fan, Y., Wang, Y., et al. (2007). Antisense RNA-mediated suppression of Bmi-1 gene expression inhibits the proliferation of lung cancer cell line A549. Oligonucleotides, 17, 327–335.PubMedCrossRefGoogle Scholar
  17. 17.
    Jacobs, J. J., Kieboom, K., Marino, S., DePinho, R. A., & van Lohuizen, M. (1999). The oncogene and Polycomb-group gene bmi-1 regulates cell proliferation and senescence through the INK4A locus. Nature, 397, 164–168.PubMedCrossRefGoogle Scholar
  18. 18.
    Haupt, Y., Alexander, W. S., Barri, G., Klinken, S. P., & Adams, J. M. (1991). Novel zinc finger gene implicated as myc collaborator by retrovirally accelerated lymphomagenesis in E mu-myc transgenic mice. Cell, 65, 753–763.PubMedCrossRefGoogle Scholar
  19. 19.
    Schwartz, Y. B., & Pirrotta, V. (2007). Polycomb silencing mechanisms and the management of genomic programmes. Nature Reviews. Genetics, 8, 9–22.PubMedCrossRefGoogle Scholar
  20. 20.
    Silva, J., García, J. M., Peña, C., García, V., Domínguez, G., Suárez, D., et al. (2006). Implication of polycomb members Bmi-1, Mel-18, and Hpc-2 in the Regulation of p16INK4a, p14ARF, h-TERT, and c-Myc expression in primary breast carcinomas. Clinical Cancer Research, 12, 6929–6936.PubMedCrossRefGoogle Scholar
  21. 21.
    Liu, Y. L., Yang, Y. M., Xu, H., & Dong, X. S. (2010). Increased expression of ubiquitin-specific protease 22 can promote cancer progression and predict therapy failure in human colorectal cancer. Journal of Gastroenterology and Hepatology, 25, 1800–1805.PubMedCrossRefGoogle Scholar
  22. 22.
    Glinsky, G. V. (2007). Stem cell origin of death-from-cancer phenotypes of human prostate and breast cancers. Stem Cell Reviews, 3, 79–93.PubMedCrossRefGoogle Scholar
  23. 23.
    Henry, K. W., Wyce, A., Lo, W. S., Duggan, L. J., Emre, N. C., Kao, C. F., et al. (2003). Transcriptional activation via sequential histone H2B ubiquitylation and deubiquitylation, mediated by SAGA-associated Ubp8. Genes and Development, 17, 2648–2663.PubMedCrossRefGoogle Scholar
  24. 24.
    Wang, H., Wang, L., Erdjument-Bromage, H., Vidal, M., Tempst, P., Jones, R. S., et al. (2004). Role of histone H2A ubiquitination in Polycomb silencing. Nature, 431, 873–878.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2011

Authors and Affiliations

  • Dong-Dong Yang
    • 1
  • Bin-Bin Cui
    • 2
  • Ling-yu Sun
    • 1
  • Hong-qun Zheng
    • 1
  • Qi Huang
    • 3
  • Jin-Xue Tong
    • 1
  • Qi-Fan Zhang
    • 1
    Email author
  1. 1.Department of OncologyThe Fourth Affiliated Hospital of Harbin Medical UniversityHarbinPeople’s Republic of China
  2. 2.Colorectal SurgeryThe Third Affiliated Hospital of Harbin Medical UniversityHarbinPeople’s Republic of China
  3. 3.Center of MorphologyHarbin Medical UniversityHarbinPeople’s Republic of China

Personalised recommendations