Loss of p53 and Ink4a/Arf cooperate in a cell autonomous fashion to induce metastasis of hepatocellular carcinoma cells
Loss of p53 and Ink4a/Arf cooperate in a cell autonomous fashion to induce metastasis of hepatocellular carcinoma cells
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DOI：
10.1158/0008-5472.can-07-0381
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发表时间：
2007-08-15
期刊：
影响因子：
11.2
通讯作者：
Lewis, Brian C.
中科院分区：
文献类型：
--
作者：
Chen, Ya-Wen;Klimstra, David S.;Lewis, Brian C.
肝细胞癌（HCC）是世界范围内癌症相关死亡的主要原因。HCC患者经常出现转移到肝脏其他区域、门静脉、淋巴结或肺的疾病，导致预后不良。因此，模型系统，允许在这种疾病的转移的分子机制的探索是非常需要的。我们在这里描述了一个转移性肝癌模型后产生的小鼠多瘤病毒中间T抗原的小鼠与肝脏特异性缺失的Trp 53肿瘤抑制基因座的体细胞引入和显示细胞自主的影响p53功能丧失对肝癌转移。我们还发现，胆管癌也在这些小鼠中发展，并且一些肿瘤显示HCC和胆管癌的特征，提示起源于肝祖细胞。Ink 4a/Arf肿瘤抑制基因位点的同时缺失加速了肿瘤的形成和转移，提示p16和p19肿瘤抑制基因在此过程中可能发挥作用。值得注意的是，从缺乏Trp 53和Ink 4a/Arf两者的肿瘤分离的肿瘤细胞系相对于仅缺乏Trp 53的那些显示增强的体外侵袭活性。因此，我们的数据说明了一个新的模型系统适合肝癌转移的分析。
Hepatocellular carcinoma (HCC) is a leading cause of cancer-related death worldwide. HCC patients frequently present with disease that has metastasized to other regions of the liver, the portal vein, lymph nodes, or lungs, leading to poor prognoses. Therefore, model systems that allow exploration of the molecular mechanisms underlying metastasis in this disease are greatly needed. We describe here a metastatic HCC model generated after the somatic introduction of the mouse polyoma virus middle T antigen to mice with liver-specific deletion of the Trp53 tumor suppressor locus and show the cell autonomous effect of p53 loss of function on HCC metastasis. We additionally find that cholangiocarcinoma also develops in these mice, and some tumors display features of both HCC and cholangiocarcinoma, suggestive of origin from liver progenitor cells. Concomitant loss of the Ink4a/Arf tumor suppressor locus accelerates tumor formation and metastasis, suggesting potential roles for the p16 and p19 tumor suppressors in this process. Significantly, tumor cell lines isolated from tumors lacking both Trp53 and Ink4a/Arf display enhanced invasion activity in vitro relative to those lacking Trp53 alone. Thus, our data illustrate a new model system amenable for the analysis of HCC metastasis.