In vivo disruption of an Rb-E2F-Ezh2 signaling loop causes bladder cancer.
In vivo disruption of an Rb-E2F-Ezh2 signaling loop causes bladder cancer.
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DOI：
10.1158/0008-5472.can-14-1218
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发表时间：
2014-11-15
期刊：
影响因子：
11.2
通讯作者：
Paramio JM
中科院分区：
文献类型：
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作者：
Santos M;Martínez-Fernández M;Dueñas M;García-Escudero R;Alfaya B;Villacampa F;Saiz-Ladera C;Costa C;Oteo M;Duarte J;Martínez V;Gómez-Rodriguez MJ;Martín ML;Fernández M;Viatour P;Morcillo MA;Sage J;Castellano D;Rodriguez-Peralto JL;de la Rosa F;Paramio JM
膀胱癌（BC）是一种高度流行的人类疾病，其中视网膜母细胞瘤（Rb）通路失活和表观遗传改变是常见事件。然而，这两个过程之间的联系仍然知之甚少。在这里，我们表明，小鼠尿路上皮中所有视网膜母细胞瘤 (Rb) 家族基因的体内失活足以启动 BC 的发展。小鼠肿瘤的表征揭示了人类 BC 的多个分子特征，包括 E2F 转录因子的激活和随后的 Ezh2 表达，以及先前确定与尿路上皮肿瘤高度相关的几种信号通路的激活。这些小鼠代表了人类高级浅表 BC 的基因定义模型。小鼠和人类膀胱肿瘤的整体转录特征揭示了显着的重叠，并证实了 Ezh2 在基因表达程序下调中的主导作用。重要的是，人类浅表 BC 患者肿瘤复发和进展的增加与 E2F 和 Ezh2 表达增加以及 Ezh2 介导的基因表达抑制有关。总的来说，我们的研究为人类高级别浅表 BC 提供了一个基因定义的模型，并证明膀胱中存在 Rb-E2F-Ezh2 轴，其破坏可以促进肿瘤的发展。
Bladder cancer (BC) is a highly prevalent human disease in which retinoblastoma (Rb) pathway inactivation and epigenetic alterations are common events. However, the connection between these two processes is still poorly understood. Here we show that the in vivo inactivation of all Retinoblastoma (Rb) family genes in the mouse urothelium is sufficient to initiate BC development. The characterization of the mouse tumors revealed multiple molecular features of human BC, including the activation of E2F transcription factor and subsequent Ezh2 expression, and the activation of several signaling pathways previously identified as highly relevant in urothelial tumors. These mice represent a genetically defined model for human high-grade superficial BC. Whole transcriptional characterizations of mouse and human bladder tumors revealed a significant overlap and confirm the predominant role for Ezh2 in the downregulation of gene expression programs. Importantly, the increased tumor recurrence and progression in human superficial BC patients is associated with increased E2F and Ezh2 expression and Ezh2-mediated gene expression repression. Collectively, our studies provide a genetically defined model for human high-grade superficial BC and demonstrate the existence of an Rb-E2F-Ezh2 axis in bladder whose disruption can promote tumor development.