MED12 overexpression is a frequent event in castration-resistant prostate cancer.
MED12 overexpression is a frequent event in castration-resistant prostate cancer.
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DOI：
10.1530/erc-14-0171
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发表时间：
2014-08
影响因子：
3.9
通讯作者：
Zaki Shaikhibrahim-;A. Offermann;M. Braun;R. Menon;I. Syring;Michael D. Nowak;Rebecca Halbach;Wenzel Vogel;C. Ruiz;T. Zellweger;C. Rentsch;M. Svensson;O. Andrén;L. Bubendorf;S. Biskup;S. Duensing;J. Kirfel;S. Perner
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文献类型：
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作者：
Zaki Shaikhibrahim-;A. Offermann;M. Braun;R. Menon;I. Syring;Michael D. Nowak;Rebecca Halbach;Wenzel Vogel;C. Ruiz;T. Zellweger;C. Rentsch;M. Svensson;O. Andrén;L. Bubendorf;S. Biskup;S. Duensing;J. Kirfel;S. Perner
在最近的一项旨在揭示前列腺癌（PCa）分子基础的研究中，Barbieri及其同事使用全外显子组测序在5.4%的原发性PCa中发现了一种新的复发突变基因MED 12。MED 12编码介体复合物的亚基，是Wnt/β-连环蛋白信号传导的转导子，与hedgehog信号传导的调节和转化生长因子β（TGFβ）-受体信号传导的调节相关。因此，这些研究促使我们研究MED 12在PCa中的相关性。MED 12，SMAD 3磷酸化和增殖标记物的表达通过免疫组织化学在来自633名患者的组织微阵列上进行评估。在PCa细胞系上进行siRNA介导的MED 12敲低，随后进行细胞增殖测定、细胞周期分析、凋亡测定和用重组TGFβ3处理。我们发现MED 12在40%（28/70）的远处转移性去势抵抗性前列腺癌（CRPC（MET））和21%（19/90）的局部复发性CRPC（CRPC（MET））中过表达，而在雄激素敏感性PCa中的频率低于11%，在良性前列腺组织中没有过表达。MED 12的表达与前列腺癌组织的高增殖活性显著相关，而MED 12的敲低降低了增殖，减少了G1-到S-期的转变，并增加了细胞周期抑制剂p27的表达。TGFβ信号传导激活与组织中MED 12核过表达相关，并导致细胞系中MED 12核表达的强烈增加。此外，MED 12敲低降低了TGFβ靶基因波形蛋白的表达。我们的研究结果表明，与雄激素敏感性PCa相比，MED 12核过表达是CRPC中的常见事件，并直接涉及TGFβ信号传导。
In a recent effort to unravel the molecular basis of prostate cancer (PCa), Barbieri and colleagues using whole-exome sequencing identified a novel recurrently mutated gene, MED12, in 5.4% of primary PCa. MED12, encoding a subunit of the Mediator complex, is a transducer of Wnt/β-catenin signaling, linked to modulation of hedgehog signaling and to the regulation of transforming growth factor beta (TGFβ)-receptor signaling. Therefore, these studies prompted us to investigate the relevance of MED12 in PCa. Expression of MED12, SMAD3 phosphorylation, and proliferation markers was assessed by immunohistochemistry on tissue microarrays from 633 patients. siRNA-mediated knockdown of MED12 was carried out on PCa cell lines followed by cellular proliferation assays, cell cycle analysis, apoptosis assays, and treatments with recombinant TGFβ3. We found nuclear overexpression of MED12 in 40% (28/70) of distant metastatic castration-resistant prostate cancer (CRPC(MET)) and 21% (19/90) of local-recurrent CRPC (CRPC(LOC)) in comparison with frequencies of less than 11% in androgen-sensitive PCa, and no overexpression in benign prostatic tissues. MED12 expression was significantly correlated with high proliferative activity in PCa tissues, whereas knockdown of MED12 decreased proliferation, reduced G1- to S-phase transition, and increased the expression of the cell cycle inhibitor p27. TGFβ signaling activation associates with MED12 nuclear overexpression in tissues and results in a strong increase in MED12 nuclear expression in cell lines. Furthermore, MED12 knockdown reduced the expression of the TGFβ target gene vimentin. Our findings show that MED12 nuclear overexpression is a frequent event in CRPC in comparison with androgen-sensitive PCa and is directly implicated in TGFβ signaling.