Syring Isabella, Klümper Niklas, Offermann Anne, Braun Martin, Deng Mario, Boehm Diana, Queisser Angela, von Mässenhausen Anne, Brägelmann Johannes, Vogel Wenzel, Schmidt Doris, Majores Michael, Schindler Anne, Kristiansen Glen, Müller Stefan C, Ellinger Jörg, Adler David, Perner Sven
Section for Prostate Cancer Research, University Hospital of Bonn, Bonn, Germany.
Institute of Pathology, University Hospital of Bonn, Bonn, Germany.
Oncotarget. 2016 Apr 26;7(17):23043-23055. doi: 10.18632/oncotarget.8469.
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.
中介体复合物是基因转录的关键调节因子，多项研究表明，在多种人类疾病，尤其是癌症中，特定亚基的表达发生了改变。然而，目前仍缺乏一项系统研究来解析中介体在不同癌症实体中的转录表达情况。因此，我们利用Oncomine数据集，对20种肿瘤实体的中介体复合物亚基（MEDs）进行了全面的电子癌症与良性对照分析。几乎所有癌症实体的转录表达谱均显示，与良性组织相比，MEDs存在差异表达。通过对包含大量样本的组织微阵列进行免疫组化染色，验证并进一步研究了肾细胞癌（RCC）中MED8和肺癌（LCa）中MED12的差异表达。透明细胞肾细胞癌（ccRCC）中的MED8与较短生存期和较高的TNM分期相关，且在转移瘤中的表达高于原发肿瘤。在体外，siRNA介导的MED8敲低显著损害了ccRCC细胞系的增殖和迁移能力，这表明MED8可能是ccRCC的一个新型治疗靶点。综上所述，我们的中介体复合物转录组被证明是识别中介体复合物组成中与癌症相关变化的有效工具，揭示了MEDs确实呈现出癌症特异性转录表达谱。
