Mdm2 protein expression is strongly associated with survival in malignant pleural mesothelioma

Our plain-English summary of Mdm2 protein expression is strongly associated with survival in malignant pleural mesothelioma, by F.D. Mairinger, R.F. Walter, S. Ting, et al (Future Oncology, 2014).

The study

• Authors: F.D. Mairinger, R.F. Walter, S. Ting, C. Vollbrecht, J. Kollmeier, S. Griff, T. Hager, T. Mairinger, D.C. Christoph, D. Theegarten, K.W. Schmid, J. Wohlschlaeger
• Journal: Future Oncology
• Published: 2014;10(6):995-1005
• Cited by: 21 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

Aims: TP53 mutations are extremely rare in malignant pleural mesothelioma (MPM). In TP53 wild-type tumors, the functional p53 protein can be inactivated by MDM2.

Materials & Methods: A total of 61 patient samples were tested for their Mdm2 and p53 protein expression levels via immunohistochemistry.

Results: This study demonstrates nuclear Mdm2 expression in three out of four mesothelioma cell lines and 21.3% of the MPM specimens investigated. After silencing of the MDM2 gene by siRNA in MPM cell lines, Mdm2 immunoexpression is lost and cells show changes indicative of severe damage. Mdm2 protein expression in MPM is detected in epithelioid and biphasic subtypes only and is significantly associated with poor survival compared with Mdm2-negative tumors. This may be explained by increased Mdm2 levels possibly leading to an increased ubiquitilation and proteasomal degradation of functional p53 protein.

Conclusion: Expression of Mdm2 is a strong prognostic factor associated with shortened overall survival in MPM.

In plain English

This laboratory study examined tumor samples from 61 patients with malignant pleural mesothelioma (MPM) taken from the database of a pathology department in Berlin, Germany. The authors stained the samples for two proteins, Mdm2 and p53, and compared Mdm2 status with how long patients survived. Survival data were available for 56 patients. They also tested four mesothelioma cell lines and switched off the MDM2 gene in two of them. After the gene was switched off, Mdm2 could no longer be detected and the cells showed signs of serious damage. Mdm2 was found in tumors from 13 patients (21.3%), and only in epithelioid tumors and the epithelioid parts of biphasic tumors. Among patients with Mdm2-negative tumors, 32% were alive at three years. No patient with an Mdm2-positive tumor was alive at three years. The authors concluded that Mdm2 expression was associated with significantly poorer survival. They noted that few sarcomatoid and biphasic tumors were studied, that their p53 test could not tell working from non-working protein, and that the study did not address asbestos exposure.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Laboratory study of archived patient tumor specimens (immunohistochemistry on tissue microarrays) with survival analysis, plus experiments on mesothelioma cell lines including MDM2 gene silencing by siRNA
• Who was studied: 61 patients with malignant pleural mesothelioma from the MPM database of the Department of Pathology, Helios Klinikum Emil von Behring, Berlin, Germany. 44 were male, 12 female and 5 of unassignable gender. Survival data were available for 56. Of these 56, 46 had epithelioid, 7 biphasic and 3 sarcomatoid tumors. Four human mesothelioma cell lines were also studied. Dates of diagnosis are not given.
• Exposure: Asbestos exposure was not studied. The factor examined was Mdm2 (and p53) protein expression in tumor tissue, measured by immunohistochemistry.
• Main results:
  • Tumors from 13 of the 61 patients (21.3%) showed Mdm2 expression: 11 scored 1+, two scored 2+ and none scored 3+.
  • Mdm2 was seen only in epithelioid tumors and in the epithelioid component of biphasic tumors. The sarcomatoid tumors (three cases) and the nonepithelioid components of biphasic tumors (seven cases) were Mdm2 negative.
  • Patients with Mdm2-negative MPM had a 3-year survival of 32%. No patients with Mdm2-positive MPM were alive after three years.
  • In Cox-regression analysis, Mdm2 expression was significantly associated with overall survival (linear scale, likelihood ratio test p = 0.005).
  • The association remained statistically significant after excluding the three patients who had pleuropneumonectomy (p = 0.013).
  • Mdm2 and p53 protein expression were negatively correlated in the patient specimens (p = 0.002; rho = -0.44).
  • No significant association was found between p53 expression and survival.
  • In cell lines, NCI-H28 and NCI-H2052 stained strongly for Mdm2 and MSTO-211H stained less strongly. NCI-H2452 was negative for both p53 and Mdm2.
  • After MDM2 gene silencing, no Mdm2 could be detected in the cells. The cells showed cytoplasmic vacuolization and membrane blebbing, which the authors interpreted as irreversible cellular damage.
• The authors' conclusion: The authors concluded that about a fifth of the investigated MPM showed nuclear Mdm2 expression, which was associated with significantly poorer survival in patients with epithelioid and biphasic MPM. They suggested that a possible explanation was Mdm2-mediated inactivation of functional p53.
• Limitations the authors state:
  • The number of sarcomatoid and biphasic tumors was relatively small (three and seven). The authors said the finding needs validation in a larger study.
  • Immunohistochemistry for p53 cannot tell whether the p53 protein detected is functional or nonfunctional.
  • A possible link between Mdm2 expression and asbestos exposure could not be addressed.

Topics

The National Library of Medicine indexes this study under subjects our site covers: Lung cancer, Mesothelioma.

Medical terms in this study, explained in our Lexicon: Pleural Mesothelioma, Immunohistochemistry, Mesothelioma, Epithelioid, Biphasic Mesothelioma, Overall Survival.

Related studies

• Combination of a p53-activating CP-31398 and an MDM2 or a FAK inhibitor produces growth suppressive effects in mesothelioma with wild-type p53 genotype — B. Zhong, M. Shingyoji, et al. (2020)
• The p53/mouse double minute 2 homolog complex deregulation in merlin-deficient tumours — S. Ammoun, M.C. Schmid, et al. (2015)
• ERCC1, MLH1, MSH2, MSH6, and βIII-tubulin: resistance proteins associated with response and outcome to platinum-based chemotherapy in malignant pleural mesothelioma — S. Ting, F.D. Mairinger, et al. (2013)
• Endothelial nitric oxide synthase is strongly expressed in malignant mesothelioma but does not associate with vascular density or the expression of VEGF, FLK1 or FLT1 — Y. Soini, A. Puhakka, et al. (2001)
• Critical review about MDM2 in cancer: Possible role in malignant mesothelioma and implications for treatment — L. Urso, F. Calabrese, et al. (2016)
• Screening of Pleural Mesotheliomas for DNA-damage Repair Players by Digital Gene Expression Analysis Can Enhance Clinical Management of Patients Receiving Platin-Based Chemotherapy — R.F. Walter, C. Vollbrecht, et al. (2016)

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