Conditional loss of uterine Pten unfailingly and rapidly induces endometrial cancer in mice.
Conditional loss of uterine Pten unfailingly and rapidly induces endometrial cancer in mice.
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DOI：
10.1158/0008-5472.can-08-1274
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发表时间：
2008-07-15
期刊：
影响因子：
11.2
通讯作者：
Dey SK
中科院分区：
文献类型：
--
作者：
Daikoku T;Hirota Y;Tranguch S;Joshi AR;DeMayo FJ;Lydon JP;Ellenson LH;Dey SK
子宫内膜癌（EMC）的病因尚不完全清楚。具有快速自发发展的 EMC 的动物模型将有助于探索癌症发生和进展的机制。 Pten+/- 小鼠目前被用作研究 EMC 的模型。这些女性出现非典型子宫内膜增生，其中约 20% 进展为 EMC。此外，肿瘤在其他器官中发展，使使用该模型专门研究 EMC 变得复杂。在这里，我们发现子宫内膜 Pten 的条件性缺失会导致所有雌性小鼠早在 1 个月大时就出现 EMC，并在 3 个月大时发生肌层浸润。相比之下，子宫内膜p53的条件性缺失在此时间范围内没有表型。子宫内膜 Pten 缺失的小鼠的寿命约为 5 个月，而子宫内膜 Pten 和 p53 联合缺失的小鼠的寿命较短，且疾病状态加剧。由于子宫内膜 Pten 纯合性缺失而导致的 EMC 如此迅速地发展，表明该器官对这种肿瘤发展的抑癌基因非常敏感。所有早期病变均表现出 Cox-2 和磷酸化 Akt 水平升高，这是实体瘤的标志。更有趣的是，转录后抑制 Cox-2 表达的两种 microRNA miR-199a* 和 miR-101a 的水平在肿瘤中与 Cox-2 上调同时下调。该小鼠模型使用 loxP-Cre 系统删除子宫内膜 Pten 和/或 p53，使我们能够详细研究 EMC 的起始和进展。这些小鼠模型具有额外的优势，因为它们模仿了人类 EMC 的几个特征。
Etiology of endometrial cancer (EMC) is not fully understood. Animal models with rapidly and spontaneously developing EMC will help explore mechanisms of cancer initiation and progression. Pten+/− mice are currently being used as a model to study EMC. These females develop atypical endometrial hyperplasia of which ~20% progresses to EMC. In addition, tumors develop in other organs, complicating the use of this model to specifically study EMC. Here we show that conditional deletion of endometrial Pten results in EMC in all female mice as early as one month of age with myometrial invasion occurring by three months. In contrast, conditional deletion of endometrial p53 had no phenotype within this time frame. While mice with endometrial Pten deletion had a lifespan of about five months, mice with combined deletion of endometrial Pten and p53 had a shorter lifespan with an exacerbated disease state. Such rapid development of EMC from homozygous loss of endometrial Pten suggests that this organ is very sensitive to this tumor suppressor gene for tumor development. All lesions at early stages exhibited elevated Cox-2 and phospho-Akt levels, hallmarks of solid tumors. More interestingly, levels of two microRNAs miR-199a* and miR-101a that post-transcriptionally inhibit Cox-2 expression, were downregulated in tumors in parallel with Cox-2 upregulation. This mouse model in which the loxP-Cre system has been used to delete endometrial Pten and/or p53 allows us to study in detail the initiation and progression of EMC. These mouse models have the added advantage since they mimic several features of human EMC.