Ecotropic viral integration site 1, a novel oncogene in prostate cancer
Ecotropic viral integration site 1, a novel oncogene in prostate cancer
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DOI：
10.1038/onc.2016.325
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发表时间：
2017-03
期刊：
影响因子：
8
通讯作者：
Angela Queisser;S. Hagedorn;H. Wang;T. Schaefer;M. Konantz;S. Alavi;M. Deng;Wenzel Vogel;A. Mässenhausen;G. Kristiansen;S. Duensing;J. Kirfel;C. Lengerke;S. Perner
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文献类型：
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作者：
Angela Queisser;S. Hagedorn;H. Wang;T. Schaefer;M. Konantz;S. Alavi;M. Deng;Wenzel Vogel;A. Mässenhausen;G. Kristiansen;S. Duensing;J. Kirfel;C. Lengerke;S. Perner
前列腺癌(PCA)是西方世界最常见的男性非皮肤癌。肿瘤抑制基因和癌基因的突变对前列腺癌的进展是重要的，而干细胞蛋白在前列腺癌发生中的作用还没有得到充分的研究。这项研究探讨了转录调控因子ECOV整合位点1(EVI1)在前列腺癌发生中的作用。EVI1被认为是造血和白血病干细胞生物学的重要调节因子。我们发现，在健康的前列腺组织中，EVI1的表达仅限于位于基底层的前列腺干细胞室，由干细胞标记CD44鉴定。相反，在包括219例原发PCa患者、淋巴结和远处转移患者的PCa进展队列中，EVI1蛋白在样本中分布不均，高表达与肿瘤进展相关(P<；0.001)，表明EVI1诱导是一个驱动事件。在功能上，短发夹状RNA介导的EVI1基因敲除抑制了人前列腺癌细胞的增殖、细胞周期进程、迁移能力和贴壁非依赖性生长，同时增强了其对凋亡的敏感性。有趣的是，EVI1表达的调节也强烈地调节干细胞的特性(包括干细胞标记物SOX2的表达)和体内肿瘤启动能力。进一步强调EVI1诱导和肿瘤进展之间的功能相关性，在实验来源的多西紫杉醇耐药的PCa细胞中发现EVI1表达上调。重要的是，这些细胞中EVI1的敲除恢复了对多西紫杉醇的敏感性，部分是通过下调抗凋亡的bcl2。综上所述，这些数据表明EVI1是一种新的前列腺癌进展和治疗耐药的分子调节因子，可能在干细胞水平上控制前列腺癌的发生。
Prostate cancer (PCa) is the most commonly diagnosed non-cutaneous cancer in men in the western world. Mutations in tumor suppressor genes and in oncogenes are important for PCa progression, whereas the role of stem cell proteins in prostate carcinogenesis is insufficiently examined. This study investigates the role of the transcriptional regulator Ecotropic Viral Integration site 1 (EVI1), known as an essential modulator of hematopoietic and leukemic stem cell biology, in prostate carcinogenesis. We show that in healthy prostatic tissue, EVI1 expression is confined to the prostate stem cell compartment located at the basal layer, as identified by the stem cell marker CD44. Instead, in a PCa progression cohort comprising 219 samples from patients with primary PCa, lymph node and distant metastases, EVI1 protein was heterogeneously distributed within samples and high expression is associated with tumor progression (P< 0.001), suggesting EVI1 induction as a driver event. Functionally, short hairpin RNA-mediated knockdown of EVI1 inhibited proliferation, cell cycle progression, migratory capacity and anchorage-independent growth of human PCa cells, while enhancing their apoptosis sensitivity. Interestingly, modulation of EVI1 expression also strongly regulated stem cell properties (including expression of the stem cell marker SOX2) and in vivo tumor initiation capacity. Further emphasizing a functional correlation between EVI1 induction and tumor progression, upregulation of EVI1 expression was noted in experimentally derived docetaxel-resistant PCa cells. Importantly, knockdown of EVI1 in these cells restored sensitivity to docetaxel, in part by downregulating anti-apoptotic BCL2. Together, these data indicate EVI1 as a novel molecular regulator of PCa progression and therapy resistance that may control prostate carcinogenesis at the stem cell level.