Mediator Complex Subunit MED1 Protein Expression Is Decreased during Bladder Cancer Progression.

Niklas Klümper,Jörg Ellinger,Isabella Syring,Stefan C. Müller,Wenzel Vogel,Doris Schmidt,Sven Perner,David Adler,Johannes Brägelmann

doi:10.3389/fmed.2017.00030

Abstract

Bladder cancer (BCa) is among the most frequent cancer entities and relevantly contributes to cancer-associated deaths worldwide. The multi-protein Mediator complex is a central regulator of the transcriptional machinery of protein-coding genes and has been described to be altered in several malignancies. MED1, a subunit of the tail module, was described to negatively modulate expression of metastasis-related genes and to be downregulated in melanoma and lung cancer. In contrast, MED1 hyperactivity was described in breast and prostate cancer, likely due its function as a hub for nuclear hormone receptors. So far, only little is known about the function of the Mediator complex in BCa. The aim of this study was therefore to investigate the role of MED1 in BCa as a prognostic biomarker and a biomarker of disease progression. The protein expression of MED1 was assessed by immunohistochemistry (IHC) on tissue microarrays from 224 patients: benign urothelium n = 31, non-muscle invasive BCa (pTis, pT1) n = 72, and muscle invasive BCa (pT2-T4) n = 121. Comprehensive clinicopathological information including follow-up were available. Quantification of MED1 protein expression was evaluated by the semiquantitative image analysis program Definiens. MED1 expression significantly decreased during BCa progression from benign urothelium to advanced BCa. Muscle invasion, the crucial step in BCa progression, was associated with low MED1 protein expression. Accordingly, decreased MED1 expression was found in primary BCa samples with positive lymphonodal status and distant metastases. Furthermore, cancer-specific survival was significantly worse in the group of low MED1 expression. Our findings show that the downregulation of MED1 is associated with muscle invasion, metastatic spread, and shorter overall survival in BCa.

Highlights

Bladder cancer (BCa) is occurring frequently with about 180,000 new cases and 40,000 deaths per year in the European Union [1]
MED1 protein expression showed a predominant nuclear localization, as the Mediator complex interacts in the nucleus with the transcriptional machinery
In non-muscle invasive BCa (NMIBC) (NMIBC = preinvasive carcinoma in situ lesions (pTis) and pT1), the expression intensity of MED1 was similar compared to the benign transitional epithelium (Figure 1B, p = 0.99), whereas in muscle-invasive tumor stages (MIBC = T2–T4), the nuclear and cytoplasmic MED1 expression was significantly decreased compared to benign bladder tissue (Figure 1C, p = 5E−05)

Summary

Introduction

Bladder cancer (BCa) is occurring frequently with about 180,000 new cases and 40,000 deaths per year in the European Union [1]. It is the fifth most common entity in men in the Western population and the most frequent of the urinary tract [1, 2]. Due to unspecific clinical symptoms, diagnosis of BCa frequently occurs at the muscle-invasive stage, which is often accompanied by distant metastases leading to unfavorable outcome. Especially, the mechanisms of enhanced motility leading to muscle invasion and metastatic spread are of great interest to achieve better outcomes in the future

Results

Discussion

Conclusion