Oncogenic HRAS Activates Epithelial-to-Mesenchymal Transition and Confers Stemness to p53-Deficient Urothelial Cells to Drive Muscle Invasion of Basal Subtype Carcinomas.
Oncogenic HRAS Activates Epithelial-to-Mesenchymal Transition and Confers Stemness to p53-Deficient Urothelial Cells to Drive Muscle Invasion of Basal Subtype Carcinomas.
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DOI：
10.1158/0008-5472.can-14-3067
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发表时间：
2015-05-15
期刊：
影响因子：
11.2
通讯作者：
Wu XR
中科院分区：
文献类型：
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作者：
He F;Melamed J;Tang MS;Huang C;Wu XR
肌层浸润性膀胱尿路上皮癌（MIUCB）表现出频繁的受体酪氨酸激酶改变，但其对肿瘤病理生理学的贡献的确切性质尚不清楚。使用突变型HRAS（HRAS*）作为致癌原型，我们在转基因小鼠中获得了证据，即尿路上皮细胞中RTK/RAS通路激活导致增生，在一年的时间内既不会进展为坦率的癌，也不会退化为正常的尿路上皮。这种持续的增生状态似乎是由促有丝分裂因子和p19-MDM 2-p53-p21轴中的补偿性肿瘤屏障之间的平衡以及延长的G2停滞引起的。表达HRAS* 的转基因小鼠的尿路上皮细胞中p53的条件性失活导致原位癌和基底亚型MIUCB，其局部鳞状分化类似于人类对应物。显微切割的MIUCB的转录组富含驱动上皮-间充质转化的基因，其上调与表达多种祖细胞/干细胞标志物的尿路上皮细胞相关。综上所述，我们的研究结果为RTK/RAS通路激活和p53缺陷作为一种组合治疗诊断生物标志物提供了证据，这可能会为尿路上皮癌的进展和治疗提供信息。
Muscle-invasive urothelial carcinomas of the bladder (MIUCB) exhibit frequent receptor tyrosine kinase alterations but the precise nature of their contributions to tumor pathophysiology is unclear. Using mutant HRAS (HRAS*) as an oncogenic prototype, we obtained evidence in transgenic mice that RTK/RAS pathway activation in urothelial cells causes hyperplasia that neither progresses to frank carcinoma nor regresses to normal urothelium through a period of one year. This persistent hyperplastic state appeared to result from an equilibrium between pro-mitogenic factors and compensatory tumor barriers in the p19-MDM2-p53-p21 axis and a prolonged G2 arrest. Conditional inactivation of p53 in urothelial cells of transgenic mice expressing HRAS* resulted in carcinoma-in-situ and basal-subtype MIUCB with focal squamous differentiation resembling the human counterpart. The transcriptome of microdissected MIUCB was enriched in genes that drive epithelial-mesenchyme transition, the upregulation of which is associated with urothelial cells expressing multiple progenitor/stem cell markers. Taken together, our results provide evidence for RTK/RAS pathway activation and p53 deficiency as a combinatorial theranostic biomarker which may inform the progression and treatment of urothelial carcinoma.