Expression of the p53 Inhibitors MDM2 and MDM4 as Outcome Predictor in Muscle-invasive Bladder Cancer

Anticancer Res. 2016 Oct;36(10):5205-5213. doi: 10.21873/anticanres.11091.


Aim: To evaluate the prognostic role of the p53-upstream inhibitors MDM2, MDM4 and its splice variant MDM4-S in patients undergoing radical cystectomy (RC) for muscle-invasive bladder cancer (MIBC).

Materials and methods: mRNA Expression levels of MDM2, MDM4 and MDM4-S were assessed by quantitative real-time polymerase chain reaction (qRT-PCR) in 75 RC samples. Logistic regression analyses identified predictors of recurrence-free (RFS) and cancer-specific survival (CSS).

Results: High expression was found in 42% (MDM2), 27% (MDMD4) and 91% (MDM4-S) of tumor specimens. Increased MDM2 expression was significantly associated with higher tumor stage (p=0.05) and lymphovascular invasion (LVI) (p=0.041). In the univariate analysis, low MDM4 expression (hazard ratio (HR)=5.93; p=0.002; HR=3.00; p=0.047), but not MDM2 (HR=1.63; p=0.222; HR=1.59; p=0.27), were associated with RFS and CSS. In the multivariate analysis, the combination of low MDM4 and high MDM2 was significant for RFS and CSS (HR=14.9; p=0.001; HR=5.63; p=0.019).

Conclusion: The combination of MDM2 and MDM4 expression is an independent predictor in patients undergoing RC for MIBC.

Keywords: HDMX; MDM2; bladder cancer; marker; prognosis.

MeSH terms

  • Aged
  • Biomarkers, Tumor / genetics
  • Cell Cycle Proteins
  • Cell Line, Tumor
  • Cystectomy
  • Female
  • Humans
  • Male
  • Muscle Neoplasms / genetics*
  • Muscle Neoplasms / secondary
  • Muscle Neoplasms / surgery
  • Muscles / pathology
  • Neoplasm Invasiveness
  • Neoplasm Recurrence, Local / pathology
  • Neoplasm Staging
  • Nuclear Proteins / genetics*
  • Prognosis
  • Proportional Hazards Models
  • Proto-Oncogene Proteins / genetics*
  • Proto-Oncogene Proteins c-mdm2 / genetics*
  • Tumor Suppressor Protein p53 / antagonists & inhibitors
  • Urinary Bladder Neoplasms / genetics*
  • Urinary Bladder Neoplasms / pathology
  • Urinary Bladder Neoplasms / surgery


  • Biomarkers, Tumor
  • Cell Cycle Proteins
  • MDM4 protein, human
  • Nuclear Proteins
  • Proto-Oncogene Proteins
  • Tumor Suppressor Protein p53
  • MDM2 protein, human
  • Proto-Oncogene Proteins c-mdm2