Hyperactivation of Ha-ras oncogene, but not Ink4a/Arf deficiency, triggers bladder tumorigenesis
Hyperactivation of Ha-ras oncogene, but not Ink4a/Arf deficiency, triggers bladder tumorigenesis
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DOI：
10.1172/jci30062
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发表时间：
2007-02-01
影响因子：
15.9
通讯作者：
Wu, Xue-Ru
中科院分区：
文献类型：
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作者：
Mo, Lan;Zheng, Xiaoyong;Wu, Xue-Ru
虽然ras是一种强有力的促有丝分裂癌基因，但其致瘤性依赖于细胞环境和协同事件。在这里，我们表明，低水平表达的一个组成型活性的Ha-ras在小鼠尿路上皮细胞诱导简单的尿路上皮增生，即使在没有Ink 4a/Arf的情况下，是抵抗发展到成熟的膀胱肿瘤。与此形成鲜明对比的是，激活的Ha-ras基因剂量加倍会引发早发型、快速生长和100%渗透的整个泌尿道肿瘤。肿瘤的发生需要取代单纯性和结节性增生之间的限速步骤，后者的标志是间充质成分的出现和AKT和STAT通路的共激活以及PTEN失活。这些结果表明，Ha-ras的过度激活是必需的，也足以诱导膀胱肿瘤沿着一个低级别的，非侵入性的乳头状通路，他们摆脱了最近的研究结果，ras激活，通过点突变，过度表达，或加强信号从FGF受体3，发生在70%-90%的这些肿瘤在人类。我们的研究结果强调了Ha-ras激活的剂量/强度在决定其致瘤性方面的至关重要性-癌基因激活的机制迄今尚未完全理解。最后，我们的研究结果具有临床意义，因为抑制ras和/或其下游效应物，如AKT和STAT 3/5，可以提供治疗低度浅表乳头状膀胱肿瘤（泌尿系统中最常见的肿瘤）的替代方法。
Although ras is a potent mitogenic oncogene, its tumorigenicity depends on cellular context and cooperative events. Here we show that low-level expression of a constitutively active Ha-ras in mouse urothelium induces simple urothelial hyperplasia that is resistant to progression to full-fledged bladder tumors even in the absence of Ink4a/Arf. In stark contrast, doubling of the gene dosage of the activated Ha-ras triggered early-onset, rapidly growing, and 100% penetrant tumors throughout the urinary tract. Tumor initiation required superseding a rate-limiting step between simple and nodular hyperplasia, the latter of which is marked by the emergence of mesenchymal components and the coactivation of AKT and STAT pathways as well as PTEN inactivation. These results indicate that overactivation of Ha-ras is both necessary and sufficient to induce bladder tumors along a low-grade, noninvasive papillary pathway, and they shed fight on the recent findings that ras activation, via point mutation, overexpression, or intensified signaling from FGF receptor 3, occurs in 70%-90% of these tumors in humans. Our results highlight the critical importance of the dosage/strength of Ha-ras activation in dictating its tumorigenicity - a mechanism of oncogene activation not fully appreciated to date. Finally, our results have clinical implications, as inhibiting ras and/or its downstream effectors, such as AKT and STAT3/5, could provide alternative means to treat low-grade, superficial papillary bladder tumors, the most common tumor in the urinary system.