Loss of p130 accelerates tumor development in a mouse model for human small-cell lung carcinoma.
Loss of p130 accelerates tumor development in a mouse model for human small-cell lung carcinoma.
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DOI：
10.1158/0008-5472.can-09-4228
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发表时间：
2010-05-15
期刊：
影响因子：
11.2
通讯作者：
Sage J
中科院分区：
文献类型：
--
作者：
Schaffer BE;Park KS;Yiu G;Conklin JF;Lin C;Burkhart DL;Karnezis AN;Sweet-Cordero EA;Sage J
小细胞肺癌（SCLC）是肺癌的神经内分泌亚型。虽然SCLC患者通常最初对治疗有反应，但肿瘤几乎总是复发，导致5年生存率低于10%。基于RB和p53肿瘤抑制基因在超过90%的人SCLC中突变的事实，已经开发了小鼠模型。在患者和小鼠模型中出现的证据表明，与RB相关的基因p130可能在SCLC细胞中充当肿瘤抑制因子。为了验证这一观点，我们使用条件突变小鼠在成年肺上皮细胞中缺失p130、Rb和p53。我们发现，p130的丢失导致在这种三重敲除小鼠模型中增殖增加和SCLC发展的显著加速。三重突变小鼠肿瘤的组织病理学特征与人SCLC的组织病理学特征非常相似。全基因组表达谱实验进一步表明Rb/p53/p130突变小鼠肿瘤与人SCLC相似。这些发现表明p130在SCLC中起关键的肿瘤抑制作用。Rb/p53/p130突变小鼠提供了一种新的临床前小鼠模型，以确定针对SCLC的新的治疗靶点。
Small cell lung carcinoma (SCLC) is a neuroendocrine subtype of lung cancer. While SCLC patients often initially respond to therapy, tumors nearly always recur, resulting in a 5-year survival rate of less than 10%. A mouse model has been developed based on the fact that the RB and p53 tumor suppressor genes are mutated in more than 90% of human SCLCs. Emerging evidence in patients and mouse models suggests that p130, a gene related to RB, may act as a tumor suppressor in SCLC cells. To test this idea, we used conditional mutant mice to delete p130 in combination with Rb and p53 in adult lung epithelial cells. We found that loss of p130 resulted in increased proliferation and significant acceleration of SCLC development in this triple knockout mouse model. The histopathological features of the triple mutant mouse tumors closely resembled that of human SCLC. Genome-wide expression profiling experiments further showed that Rb/p53/p130 mutant mouse tumors were similar to human SCLC. These findings indicate that p130 plays a key tumor suppressor role in SCLC. Rb/p53/p130 mutant mice provide a novel pre-clinical mouse model to identify novel therapeutic targets against SCLC.