Induction of intrahepatic cholangiocellular carcinoma by liver-specific disruption of Smad4 and Pten in mice
Induction of intrahepatic cholangiocellular carcinoma by liver-specific disruption of Smad4 and Pten in mice
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DOI：
10.1172/jci27282
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发表时间：
2006-07-01
影响因子：
15.9
通讯作者：
Deng, Chu-Xia
中科院分区：
文献类型：
--
作者：
Xu, Xiaoling;Kobayashi, Shogo;Deng, Chu-Xia
胆管细胞癌（CC）是第二常见的原发性肝癌，预后不良。它已被证明，CC港的一些肿瘤抑制基因和癌基因的改变，但肿瘤发生的关键调控仍然未知。在这里，我们已经产生了一个小鼠模型，使用肿瘤抑制因子SMAD 4和PTEN的fiver特异性靶向破坏，以高转移率发展CC。在缺乏SMAD 4和PTEN的情况下，增生灶仅出现在2月龄的突变小鼠的胆管中，并继续生长，导致4-7月龄的所有动物中的肿瘤形成。我们发现CC的形成遵循与显著改变相关的组织病理学变化的多步骤进展，包括磷酸化AKT、FOXO 1、GSK-3 β、mTOR和ERK水平的增加以及细胞周期蛋白D1的核水平的增加。我们进一步证明SMAD 4和PTEN通过一种新的反馈机制相互调节，以维持表达平衡并协同抑制CC形成。最后，我们对人CC的分析在大多数p-AKT阳性CC中检测到PTEN失活，而大约一半也失去了SMAD 4表达。这些发现阐明了SMAD 4和PTEN之间的关系，并扩展了我们对CC形成的理解。
Cholangiocellular carcinoma (CC), the second most common primary liver cancer, is associated with a poor prognosis. It has been shown that CCs harbor alterations of a number of tumor-suppressor genes and oncogenes, yet key regulators for tumorigenesis remain unknown. Here we have generated a mouse model that develops CC with high penetrance using fiver-specific targeted disruption of tumor suppressors SMAD4 and PTEN. In the absence of SMAD4 and PTEN, hyperplastic foci emerge exclusively from bile ducts of mutant mice at 2 months of age and continue to grow, leading to tumor formation in all animals at 4-7 months of age. We show that CC formation follows a multistep progression of histopathological changes that are associated with significant alterations, including increased levels of phosphorylated AKT, FOXO1, GSK-3 beta, mTOR, and ERK and increased nuclear levels of cyclin D1. We further demonstrate that SMAD4 and PTEN regulate each other through a novel feedback mechanism to maintain an expression balance and synergistically repress CC formation. Finally, our analysis of human CC detected PTEN inactivation in a majority of p-AKT-positive CCs, while about half also lost SMAD4 expression. These findings elucidate the relationship between SMAD4 and PTEN and extend our understanding of CC formation.