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MED15, encoding a s...
MED15, encoding a subunit of the mediator complex, is overexpressed at high frequency in castration-resistant prostate cancer
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- Shaikhibrahim, Zaki (författare)
- Dept Prostate Canc Res, Univ Hosp, Bonn, Germany; Inst Pathol, Univ Hosp, Bonn, Germany
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- Menon, Roopika (författare)
- Dept Prostate Canc Res, Univ Hosp, Bonn, Germany; Inst Pathol, Univ Hosp, Bonn, Germany
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- Braun, Martin (författare)
- Dept Prostate Canc Res, Univ Hosp, Bonn, Germany; Inst Pathol, Univ Hosp, Bonn, Germany
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- Offermann, Anne (författare)
- Dept Prostate Canc Res, Univ Hosp, Bonn, Germany; Inst Pathol, Univ Hosp, Bonn, Germany
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- Queisser, Angela (författare)
- Dept Prostate Canc Res, Univ Hosp, Bonn, Germany; Inst Pathol, Univ Hosp, Bonn, Germany
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- Boehm, Diana (författare)
- Dept Prostate Canc Res, Univ Hosp, Bonn, Germany; Inst Pathol, Univ Hosp, Bonn, Germany
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- Vogel, Wenzel (författare)
- Dept Prostate Canc Res, Univ Hosp, Bonn, Germany; Inst Pathol, Univ Hosp, Bonn, Germany
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- Rueenauver, Kerstin (författare)
- Dept Prostate Canc Res, Univ Hosp, Bonn, Germany; Inst Pathol, Univ Hosp, Bonn, Germany
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- Ruiz, Christian (författare)
- Inst Pathol, Univ Basel Hosp, Basel, Switzerland
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- Zellweger, Tobias (författare)
- Dept Urol, St Clara Hosp, Basel, Switzerland
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- Svensson, Maria (författare)
- Region Örebro län,Dept Urol, Örebro University Hospital, Örebro, Sweden
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- Andrén, Ove, 1963- (författare)
- Region Örebro län,Örebro universitet, Institutionen för hälsovetenskap och medicin,Dept Urol, Örebro University Hospital, Örebro, Sweden
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- Kristiansen, Glen (författare)
- Inst Pathol, Univ Hosp, Bonn, Germany
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- Wernert, Nicolas (författare)
- Inst Pathol, Univ Hosp, Bonn, Germany
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- Bubendorf, Lukas (författare)
- Inst Pathol, Univ Basel Hosp, Basel, Switzerland
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- Kirfel, Jutta (författare)
- Inst Pathol, Univ Hosp, Bonn, Germany
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- Biskup, Saskia (författare)
- Ctr Genom & Transcript, CeGaT GmbH, Tubingen, Germany
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- Perner, Sven (författare)
- Dept Prostate Canc Res, Univ Hosp, Bonn, Germany; Inst Pathol, Univ Hosp, Bonn, Germany
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(creator_code:org_t)
- 2013-12-09
- 2014
- Engelska.
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Ingår i: International Journal of Cancer. - Hoboken : Wiley-Blackwell. - 0020-7136 .- 1097-0215. ; 135:1, s. 19-26
- Relaterad länk:
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https://onlinelibrar...
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https://urn.kb.se/re...
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https://doi.org/10.1...
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Abstract
Ämnesord
Stäng
- The mediator complex is an evolutionary conserved key regulator of transcription of protein-coding genes and an integrative hub for diverse signaling pathways. In this study, we investigated whether the mediator subunit MED15 is implicated in castration-resistant prostate cancer (CRPC). MED15 expression and copy number/rearrangement status were assessed by immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH), respectively on 718 prostate cancer (PCa) specimens and sequenced by Sanger on a subset. Furthermore, SMAD3 phosphorylation, androgen receptor (AR) and proliferation markers were evaluated by IHC. In PCa cells, siRNA/shRNA knockdown of MED15 was followed by proliferation assays with/without dihydrotestosterone (DHT), and treatments with recombinant TGF-beta 3. Our results show that MED15 is overexpressed in 76% of distant metastatic CRPC (CRPCMET) and 70% of local-recurrent CRPC (CRPCLOC), in contrast to low frequencies in androgen-sensitive PCa, and no expression in benign prostatic tissue. Furthermore, MED15 overexpression correlates with worse clinical outcome thus defining a highly lethal phenotype. Moreover, TGF-beta signaling activation associates with MED15 overexpression in PCa tissues, and leads to increased expression of MED15 in PCa cells. MED15 knockdown effects phosphorylation and shuttling of p-SMAD3 to the nucleus as well as TGF-beta-enhanced proliferation. In PCa tissues, MED15 overexpression associates with AR overexpression/amplification and correlates with high proliferative activity. MED15 knockdown decreases both androgen-dependent and -independent proliferation in PCa cells. Taken together, these findings implicate MED15 in CRPC, and as MED15 is evolutionary conserved, it is likely to emerge as a lethal phenotype in other therapeutic-resistant diseases, and not restricted to our disease model.
Ämnesord
- MEDICIN OCH HÄLSOVETENSKAP -- Klinisk medicin -- Cancer och onkologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Clinical Medicine -- Cancer and Oncology (hsv//eng)
Nyckelord
- castration-resistant
- prostate cancer
- MED15
- TGF-beta
- Onkologi
- Oncology
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- ref (ämneskategori)
- art (ämneskategori)
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Shaikhibrahim, Z ...
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Menon, Roopika
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Braun, Martin
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Offermann, Anne
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Queisser, Angela
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Boehm, Diana
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visa fler...
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Vogel, Wenzel
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Rueenauver, Kers ...
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Ruiz, Christian
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Zellweger, Tobia ...
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Svensson, Maria
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Andrén, Ove, 196 ...
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Kristiansen, Gle ...
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Wernert, Nicolas
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Bubendorf, Lukas
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Kirfel, Jutta
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Biskup, Saskia
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Perner, Sven
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