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

Abstract

IntroductionBladder 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.MethodsThe 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.ResultsMED1 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.ConclusionOur findings show that the downregulation of MED1 is associated with muscle invasion, metastatic spread, and shorter overall survival in BCa.

The Contrasting Role of the Mediator Subunit MED30 in the Progression of Bladder Cancer

“…The reduction of theses parameters after the knockdown suggest an oncogenic impact of MED30 in bladder carcinoma. The role as a tumour suppressor has already been described for other subunits such as MED1 in melanoma (24), lung cancer (25,26) and urothelial cancer (27). In melanoma, the down-regulation of the tail module MED1 triggers a strong tumorigenic phenotype (24) and is associated with worse outcome in lung adenocarcinoma (25).…”

“…The reason for this can be found in the connection to different signalling pathways (like Wnt-or TGFβ-signalling pathway) or to further transcription factors (coactivators vs. inhibitors). Additionally, a possible explanation might be that some subunits, such as MED1, as coactivators of nuclear hormone receptors, are necessary in hormone-dependent tumours such as prostate (29) or breast cancer (30), whereas in other cancer entities such as melanoma (24), lung cancer (25) and BCa (27), downregulation of MED1 increases tumorigenic potential by modulating metastasis-related genes such as uPAR.…”

The knockdown of the Mediator complex subunit MED15 restrains urothelial bladder cancer cells' malignancy

“…Additionally, the knockdown of MED19 leads to a reduced growth of the carcinoma cell lines ( 14 ). Contrary to this, the expression of MED1 significantly decreases during BCa progression from benign urothelium to advanced BCa, and cancer-specific survival (CSS) was significantly worse in the group that had low MED1 expression ( 15 ).…”

A functional genetic screen identifies the Mediator complex as essential for SSX2-induced senescence

“…These results were consistent with a previous study reporting that MED1 was often either upregulated or downregulated in melanoma 36 , which also showed that low MED1 expression correlated with a highly tumorigenic phenotype. Multiple other studies have also demonstrated that MED1 31,[37][38][39][40][41] and Mediator subunits are deregulated in melanoma and other cancer types 31,[42][43][44][45][46] . The observed differences in expression of different MEDs may translate into diffences in the activity of the Mediator complex to support tumorigenesis and specific phenotypes, such as SSX2 expression.…”