β-Catenin activation synergizes with PTEN loss to cause bladder cancer formation.
β-Catenin activation synergizes with PTEN loss to cause bladder cancer formation.
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DOI：
10.1038/onc.2010.399
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发表时间：
2011-01-13
期刊：
影响因子：
8
通讯作者：
Sansom, O. J.
中科院分区：
文献类型：
--
作者：
Ahmad, I.;Morton, J. P.;Singh, L. B.;Radulescu, S. M.;Ridgway, R. A.;Patel, S.;Woodgett, J.;Winton, D. J.;Taketo, M. M.;Wu, X-R;Leung, H. Y.;Sansom, O. J.
尽管Wnt信号通路的失调与尿路上皮细胞癌（UCC）有关，但其功能意义尚不清楚。为了测试其重要性，我们使用Cre-Lox技术（UroIICRE+ β-连环蛋白3/+）将β-连环蛋白的活化形式靶向表达至转基因小鼠的尿道。这种激活形式的β-连环蛋白的表达导致3个月时形成局部过度增生性病变，但并未进展为恶性肿瘤。这些病变的特点是显着增加的PTEN肿瘤抑制蛋白。这似乎是膀胱中激活Wnt信号传导的直接结果，因为成人膀胱内Apc（腺瘤性结肠息肉病）基因的条件性缺失迅速导致β-连环蛋白和PTEN同时表达。该PTEN表达阻断增殖。接下来，我们将PTEN缺陷与β-catenin激活相结合，发现这导致了乳头状UCC。这些肿瘤具有增加的pAKT信号传导并且依赖于mTOR。重要的是，在人类UCC中，高水平的β-连环蛋白和pAKT（以及低水平的PTEN）之间存在显著相关性。总之，这些数据明确表明，失调的Wnt信号传导在驱动UCC中起关键作用，并表明具有高水平Wnt和PI 3激酶信号传导的人UCC可能对mTOR抑制有反应。
Although deregulation of the Wnt signalling pathway has been implicated in urothelial cell carcinoma (UCC), the functional significance is unknown. To test its importance, we have targeted expression of an activated form of β-catenin to the urothelium of transgenic mice using Cre-Lox technology (UroIICRE+ β-cateninexon3/+). Expression of this activated form of β-catenin led to the formation of localised hyperproliferative lesions by 3 months, which did not progress to malignancy. These lesions were characterised by a marked increase of the PTEN tumour suppressor protein. This appears to be a direct consequence of activating Wnt signalling in the bladder as conditional deletion of the Apc (Adenomatous Polyposis coli) gene within the adult bladder led rapidly to coincident β-catenin and PTEN expression. This PTEN expression blocked proliferation. Next, we combined PTEN deficiency with β-catenin activation and found this caused papillary UCC. These tumours had increased pAKT signalling and were dependent on mTOR. Importantly in human UCC, there was a significant correlation between high levels of β-catenin and pAKT (and low levels of PTEN). Taken together these data definitively show that deregulated Wnt signalling plays a critical role in driving UCC, and suggests that human UCC which have high levels of Wnt and PI3 kinase signalling may be responsive to mTOR inhibition.
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