Increased mediator complex subunit CDK19 expression associates with aggressive prostate cancer
Increased mediator complex subunit CDK19 expression associates with aggressive prostate cancer
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DOI：
10.1002/ijc.32551
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发表时间：
2019-07-19
影响因子：
6.4
通讯作者：
Offermann, Anne
中科院分区：
文献类型：
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作者：
Becker, Finn;Joerg, Vincent;Offermann, Anne
介体复合物是与转录因子和RNA聚合酶II相互作用的转录调节因子。最近，我们确定其亚基CDK 19在前列腺癌（PCa）中特异性表达，并在功能上与PCa侵袭性有关。本研究的目的是全面地表征PCa中CDK 19及其副产物CDK 8的蛋白表达。我们对一个大的队列进行了CDK 19/CDK 8的免疫组化（IHC），包括202例患者的针吸活检，415例患者的799个根治性膀胱癌切除术标本的原发肿瘤病灶，120个通过姑息性经尿道切除术获得的局部晚期肿瘤病灶，140个淋巴结转移，67个远处转移和82个良性肿瘤。对原发性肿瘤进行增殖标记物Ki 67、雄激素受体（AR）和ERG染色。对于376例患者，临床病理数据可用。主要终点是无疾病复发生存期（DFS）。细胞核CDK 19和CDK 8表达在进展过程中增加，在转移性和去势抵抗性肿瘤中显示最高强度。原发性肿瘤中CDK 19的高表达与DFS相关，与Gleason分级和PSA无关。原发性肿瘤不表达、中度表达和高度表达CDK 19的患者的5年DFS率分别为73.7%、56.9%和30.4%。CDK 19与Gleason分级、T分期、Ki 67增殖指数、核AR表达和ERG状态相关。转移性和去势抵抗性前列腺癌的治疗选择仍然有限。在目前的研究中，我们证实了介体亚基CDK 19在晚期PCa中的重要作用，支持了目前针对CDK 19及其副产物CDK 8的发展。此外，CDK 19蛋白表达具有独立于已建立的生物标志物预测疾病复发的潜力，从而有助于PCa患者的个体化管理。
The Mediator complex is a transcriptional regulator interacting with transcription factors and RNA-polymerase-II. Recently, we identified its subunit CDK19 to be specifically expressed in prostate cancer (PCa) and to be functionally implicated in PCa aggressiveness. Aim of our study was to comprehensively characterize the protein expression of CDK19 and its paralog CDK8 in PCa. We performed immunohistochemistry (IHC) for CDK19/CDK8 on a large cohort including needle biopsies from 202 patients, 799 primary tumor foci of radical prostatectomy specimens from 415 patients, 120 locally advanced tumor foci obtained by palliative transurethral resection, 140 lymph node metastases, 67 distant metastases and 82 benigns. Primary tumors were stained for the proliferation marker Ki67, androgen receptor (AR) and ERG. For 376 patients, clinic-pathologic data were available. Primary endpoint was disease-recurrence-free survival (DFS). Nuclear CDK19 and CDK8 expression increases during progression showing the highest intensity in metastatic and castration-resistant tumors. High CDK19 expression on primary tumors correlates with DFS independently from Gleason grade and PSA. Five-year-DFS rates of patients with primary tumors expressing no, moderate and high CDK19 are 73.7, 56.9 and 30.4%, respectively. CDK19 correlates with Gleason grade, T-stage, Ki67 proliferation-index, nuclear AR expression and ERG-status. Therapeutic options for metastatic and castration-resistant PCa remain limited. In the current study, we confirmed an important role of the Mediator subunit CDK19 in advanced PCa supporting current developments to target CDK19 and its paralog CDK8. Furthermore, CDK19 protein expression has the potential to predict disease recurrence independently from established biomarkers thus contributing to individual management for PCa patients.