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  • 1
    Language: English
    In: The Journal of Urology, April 2015, Vol.193(4), pp.e860-e860
    Description: To link to full-text access for this article, visit this link: http://dx.doi.org/10.1016/j.juro.2015.02.2469 Byline: Isabella Syring, Niklas Klumper, Zaki Shaikhibrahim, Anne Offermann, Martin Braun, Mario Deng, Diana Bohm, Angela Queisser, Anne von Ma[sz]enhausen, Jorg Ellinger, Stefan C. Muller, Sven Perner Author Affiliation: Bonn, Germany Article Note: (footnote) Source of Funding: none
    Keywords: Medicine
    ISSN: 0022-5347
    E-ISSN: 1527-3792
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  • 2
    Language: English
    In: Clinical cancer research : an official journal of the American Association for Cancer Research, 01 April 2017, Vol.23(7), pp.1829-1840
    Description: The Mediator complex is a multiprotein assembly, which serves as a hub for diverse signaling pathways to regulate gene expression. Because gene expression is frequently altered in cancer, a systematic understanding of the Mediator complex in malignancies could foster the development of novel targeted therapeutic approaches. We performed a systematic deconvolution of the Mediator subunit expression profiles across 23 cancer entities ( = 8,568) using data from The Cancer Genome Atlas (TCGA). Prostate cancer-specific findings were validated in two publicly available gene expression cohorts and a large cohort of primary and advanced prostate cancer ( = 622) stained by immunohistochemistry. The role of and was evaluated by siRNA-mediated gene knockdown and inhibitor treatment in prostate cancer cell lines with functional assays and gene expression analysis by RNAseq. Cluster analysis of TCGA expression data segregated tumor entities, indicating tumor-type-specific Mediator complex compositions. Only prostate cancer was marked by high expression of In primary prostate cancer, was associated with increased aggressiveness and shorter disease-free survival. During cancer progression, highest levels of CDK19 and of its paralog CDK8 were present in metastases. , inhibition of CDK19 and CDK8 by knockdown or treatment with a selective CDK8/CDK19 inhibitor significantly decreased migration and invasion. Our analysis revealed distinct transcriptional expression profiles of the Mediator complex across cancer entities indicating differential modes of transcriptional regulation. Moreover, it identified and to be specifically overexpressed during prostate cancer progression, highlighting their potential as novel therapeutic targets in advanced prostate cancer. .
    Keywords: Cyclin-Dependent Kinase 8 -- Genetics ; Cyclin-Dependent Kinases -- Genetics ; Mediator Complex -- Genetics ; Prostatic Neoplasms -- Genetics
    ISSN: 1078-0432
    E-ISSN: 15573265
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  • 3
    Language: English
    In: Frontiers in medicine, 2017, Vol.4, pp.30
    Description: 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  = 31, non-muscle invasive BCa (pTis, pT1)  = 72, and muscle invasive BCa (pT2-T4)  = 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.
    Keywords: Med1 ; Bladder Cancer ; Immunohistochemistry ; Mediator ; Mediator Complex
    ISSN: 2296-858X
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  • 4
    Language: English
    In: Molecular cancer, 02 February 2016, Vol.15, pp.10
    Description: Clear cell renal cell carcinoma (ccRCC) is among the most common human malignancies. In order to provide better understanding of the molecular biology of ccRCC and to identify potential diagnostic/prognostic biomarker and therapeutic targets, we utilized a microarray to profile mRNA expression of corresponding normal and malignant renal tissues. Real-time PCR, Western Blot and immunohistochemistry were applied to study the expression of candidate biomarkers. ccRCC cell lines were treated with sertraline to inhibit the dopamine transporter SLC6A3. Differential expression of fourteen mRNAs, yet not studied in ccRCC in depth, was confirmed using qPCR (upregulation: SLC6A3, NPTX2, TNFAIP6, NDUFA4L2, ENPP3, FABP6, SPINK13; downregulation: FXYD4, SLC12A1, KNG1, NPHS2, SLC13A3, GCGR, PLG). Up-/downregulation was also confirmed for FXYD4, KNG1, NPTX2 and SLC12A1 by Western Blot on the protein level. In contrast to the mRNA expression, protein expression of the dopamine transporter SLC6A3 was lower in ccRCC compared to normal renal tissue. Immunohistochemistry indicated that this decrease was due to higher concentrations of SLC6A3 in the proximal tubules. Immunohistochemical analyses further demonstrated that high SLC6A3 expression in ccRCC tissue was correlated with a shorter period of recurrence-free survival following surgery. Treatment of ccRCC cells with the SLC6A3 inhibitor sertraline induced dose-dependent cell-death. Our study identified several novel biomarkers with diagnostic potential and further investigations on sertraline as therapeutic agent in ccRCC patients are warranted.
    Keywords: Biomarkers, Tumor -- Genetics ; Carcinoma, Renal Cell -- Genetics ; Kidney Neoplasms -- Genetics
    E-ISSN: 1476-4598
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  • 5
    Language: English
    In: Diagnostic pathology, 17 September 2015, Vol.10, pp.165
    Description: Testicular germ cell tumors (TGCT) are the most common cancer entities in young men with increasing incidence observed in the last decades. For therapeutic management it is important, that TGCT are divided into several histological subtypes. MED15 is part of the multiprotein Mediator complex which presents an integrative hub for transcriptional regulation and is known to be deregulated in several malignancies, such as prostate cancer and bladder cancer role, whereas the role of the Mediator complex in TGCT has not been investigated so far. Aim of the study was to investigate the implication of MED15 in TGCT development and its stratification into histological subtypes. Immunohistochemical staining (IHC) against Mediator complex subunit MED15 was conducted on a TGCT cohort containing tumor-free testis (n = 35), intratubular germ cell neoplasia unclassified (IGCNU, n = 14), seminomas (SEM, n = 107) and non-seminomatous germ cell tumors (NSGCT, n = 42), further subdivided into embryonic carcinomas (EC, n = 30), yolk sac tumors (YST, n = 5), chorionic carcinomas (CC, n = 5) and teratomas (TER, n = 2). Quantification of MED15 protein expression was performed through IHC followed by semi-quantitative image analysis using the Definiens software. In tumor-free seminiferous tubules, MED15 protein expression was absent or only low expressed in spermatogonia. Interestingly, the precursor lesions IGCNU exhibited heterogeneous but partly very strong MED15 expression. SEM weakly express the Mediator complex subunit MED15, whereas NSGCT and especially EC show significantly enhanced expression compared to tumor-free testis. In conclusion, MED15 is differentially expressed in tumor-free testis and TGCT. While MED15 is absent or low in tumor-free testis and SEM, NSGCT highly express MED15, hinting at the diagnostic potential of this marker to distinguish between SEM and NSGCT. Further, the precursor lesion IGCNU showed increased nuclear MED15 expression in the preinvasive precursor cells, which may provide diagnostic value to distinguish between benign and pre-malignant testicular specimen, and may indicate a role for MED15 in carcinogenesis in TGCT.
    Keywords: Biomarkers, Tumor -- Analysis ; Mediator Complex -- Biosynthesis ; Neoplasms, Germ Cell and Embryonal -- Pathology ; Testicular Neoplasms -- Pathology
    E-ISSN: 1746-1596
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  • 6
    Language: English
    In: American journal of cancer research, 2015, Vol.5(9), pp.2816-22
    Description: Like other cancers, renal cell carcinoma (RCC) derives the essential energy for proliferation and survival from high rates of glycolysis rather than from oxidative phosphorylation of the mitochondrial respiration pathway. NDUFA4 (NADH Dehydrogenase (Ubiquinone) 1 Alpha Subcomplex, 4) is encoding a protein belonging to the respiratory chain of mitochondria. For a better understanding of the tumor biology and for identification of a potential new biomarker, we analyzed the regulation of NDUFA4 in RCC compared to normal tissue cells. Downregulation of NDUFA4 mRNA and protein was detected in RCC compared to normal renal tissues in quantitative real-time PCR as well as in western blot and immunohistochemical staining. Histological analysis revealed higher NDUFA4 expression in the distal tubules compared to the proximal tubules and the loop of Henle. A higher molecular weight of the NDUFA4 protein was discovered in RCC samples, possibly indicating a posttranslational modification. Moreover, NDUFA4 protein expression was predictive for cancer-specific survival. Our analysis revealed a potential new biomarker, but future studies are warranted to investigate the prognostic value of NDUF4A expression.
    Keywords: Ndfua4 ; Renal Cell Carcinoma ; Biomarker ; Electron Transport Chain ; Mitochondria
    ISSN: 2156-6976
    Source: MEDLINE/PubMed (U.S. National Library of Medicine)
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  • 7
    Language: English
    In: Translational Oncology, August 2017, Vol.10(4), pp.661-668
    Description: Mitochondrial dysfunction is common in cancer and the mitochondrial electron transport chain is often affected in carcinogenesis. To date, little is known about the expression of the ATP synthase subunits in clear cell renal cell carcinoma (ccRCC). The NextBio database was used to determine an expression profile of the ATP synthase subunits based on published microarray studies. We observed down-regulation of 23 out of 29 subunits of the ATP synthase. Differential expression was validated exemplarily for 12 genes ( ; screening cohort ccRCC n = 18 and normal renal tissue n = 10) using real-time PCR. Additional eight genes ( ) were internally validated within an enlarged cohort (ccRCC n = 74; normal renal tissue n = 36). Furthermore, down-regulation of ATP5A1, ATPAF1, ATP5G1/G2/G3 was confirmed on the protein level using Western Blot and immunohistochemistry. We observed that altered expression of ATPAF1 and ATP5G1/G2/G3 was correlated with overall survival in patients with ccRCC. In conclusion, down-regulation of many ATP Synthase subunits occurs in ccRCC and is the basis for the reduced activity of the mitochondrial electron chain. Alteration of the expression of ATP5A1, ATPAF1, and ATP5G1/G2/G3 is characteristic for ccRCC and may be prognostic for ccRCC patients' outcome.
    Keywords: Medicine
    ISSN: 1936-5233
    E-ISSN: 1936-5233
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  • 8
    Language: English
    In: Oncotarget, 26 April 2016, Vol.7(17), pp.23043-55
    Description: The Mediator complex is a key regulator of gene transcription and several studies demonstrated altered expressions of particular subunits in diverse human diseases, especially cancer. However a systematic study deciphering the transcriptional expression of the Mediator across different cancer entities is still lacking.We therefore performed a comprehensive in silico cancer vs. benign analysis of the Mediator complex subunits (MEDs) for 20 tumor entities using Oncomine datasets. The transcriptional expression profiles across almost all cancer entities showed differentially expressed MEDs as compared to benign tissue. Differential expression of MED8 in renal cell carcinoma (RCC) and MED12 in lung cancer (LCa) were validated and further investigated by immunohistochemical staining on tissue microarrays containing large numbers of specimen. MED8 in clear cell RCC (ccRCC) associated with shorter survival and advanced TNM stage and showed higher expression in metastatic than primary tumors. In vitro, siRNA mediated MED8 knockdown significantly impaired proliferation and motility in ccRCC cell lines, hinting at a role for MED8 to serve as a novel therapeutic target in ccRCC. Taken together, our Mediator complex transcriptome proved to be a valid tool for identifying cancer-related shifts in Mediator complex composition, revealing that MEDs do exhibit cancer specific transcriptional expression profiles.
    Keywords: Med8 ; Mediator Complex ; Pathology Section ; Cancer ; Oncomine ; Transcriptional Profile ; Gene Expression Regulation, Neoplastic ; Transcriptome ; Biomarkers, Tumor -- Genetics ; Mediator Complex -- Genetics ; Neoplasms -- Classification
    E-ISSN: 1949-2553
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  • 9
    Language: English
    In: Oncotarget, 28 February 2017, Vol.8(9), pp.14719-14735
    Description: Melanoma associated antigens (MAGE) are potential targets for immunotherapy and have been associated with poor overall survival (OS) in head and neck squamous cell carcinoma (HNSCC). However, little is known about MAGE in lymph node metastases (LNM) and recurrent disease (RD) of HNSCC.To assess whether MAGE expression increases with metastasis or recurrence, a tissue microarray (TMA) of 552 primary tumors (PT), 219 LNM and 75 RD was evaluated by immunohistochemistry for MAGE antigens using three monoclonal antibodies to multiple MAGE family members. Mean expression intensity (MEI) was obtained from triplicates of each tumor specimen.The median MEI compared between PT, LNM and RD was significantly higher in LNM and RD. In paired samples, MEI was comparable in PT to respective LNM, but significantly different from RD. Up to 25% of patients were negative for pan-MAGE or MAGE-A3/A4 in PT, but positive in RD. The prognostic impact of MAGE expression was validated in the TMA cohort and also in TCGA data (mRNA). OS was significantly lower for patients expressing pan-MAGE or MAGE-A3/A4 in both independent cohorts.MAGE expression was confirmed as a prognostic marker in HNSCC and may be important for immunotherapeutic strategies as a shared antigen.
    Keywords: Hnscc ; Mage ; Cancer-Testis Antigens ; Head and Neck Squamous Cell Carcinoma ; Melanoma-Associated Antigen ; Carcinoma, Squamous Cell -- Therapy ; Head and Neck Neoplasms -- Therapy ; Immunotherapy -- Methods ; Melanoma-Specific Antigens -- Metabolism
    E-ISSN: 1949-2553
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  • 10
    Language: English
    In: Molecular cancer research : MCR, November 2016, Vol.14(11), pp.1110-1123
    Description: KRAS-mutant lung adenocarcinoma is among the most common cancer entities and, in advanced stages, typically displays poor prognosis due to acquired resistance against chemotherapy, which is still largely based on cisplatin-containing combination regimens. Mechanisms of cisplatin resistance have been extensively investigated, and ERCC1 has emerged as a key player due to its central role in the repair of cisplatin-induced DNA lesions. However, clinical data have not unequivocally confirmed ERCC1 status as a predictor of the response to cisplatin treatment. Therefore, we employed an autochthonous mouse model of Kras-driven lung adenocarcinoma resembling human lung adenocarcinoma to investigate the role of Ercc1 in the response to cisplatin treatment. Our data show that Ercc1 deficiency in Tp53-deficient murine lung adenocarcinoma induces a more aggressive tumor phenotype that displays enhanced sensitivity to cisplatin treatment. Furthermore, tumors that relapsed after cisplatin treatment in our model develop a robust etoposide sensitivity that is independent of the Ercc1 status and depends solely on previous cisplatin exposure. Our results provide a solid rationale for further investigation of the possibility of preselection of lung adenocarcinoma patients according to the functional ERCC1- and mutational TP53 status, where functionally ERCC1-incompetent patients might benefit from sequential cisplatin and etoposide chemotherapy. This study provides a solid rationale for the stratification of lung adenocarcinoma patients according to the functional ERCC1- and mutational TP53 status, where functionally ERCC1-incompetent patients could benefit from sequential cisplatin and etoposide chemotherapy. Mol Cancer Res; 14(11); 1110-23. ©2016 AACR.
    Keywords: Adenocarcinoma -- Drug Therapy ; Cisplatin -- Administration & Dosage ; DNA-Binding Proteins -- Deficiency ; Endonucleases -- Deficiency ; Lung Neoplasms -- Drug Therapy ; Proto-Oncogene Proteins P21(Ras) -- Genetics ; Tumor Suppressor Protein P53 -- Genetics
    E-ISSN: 1557-3125
    Source: MEDLINE/PubMed (U.S. National Library of Medicine)
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