Molecular and functional characteristics of ovarian surface epithelial cells transformed by KrasG12D and loss of Pten in a mouse model in vivo.
Molecular and functional characteristics of ovarian surface epithelial cells transformed by KrasG12D and loss of Pten in a mouse model in vivo.
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DOI：
10.1038/onc.2011.70
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发表时间：
2011-08-11
期刊：
影响因子：
8
通讯作者：
Richards JS
中科院分区：
文献类型：
--
作者：
Mullany LK;Fan HY;Liu Z;White LD;Marshall A;Gunaratne P;Anderson ML;Creighton CJ;Xin L;Deavers M;Wong KK;Richards JS
卵巢癌是一种复杂且致命的疾病，在早期可治愈阶段仍然难以发现。此外，尽管已知一些在卵巢癌中经常突变、缺失或扩增的致癌途径（Kras、Pten/PI3K 和 Trp53），但这些途径如何启动和驱动特定的形态表型和肿瘤结果仍不清楚。我们最近生成了 Pten fl/fl； KrasG12D；Amhr2-Cre 小鼠破坏 Pten 基因并在卵巢表面上皮 (OSE) 细胞中表达 KrasG12D 的稳定突变形式。根据组织病理学标准，突变小鼠在幼年时就发展为低级别卵巢浆液性乳头状腺癌，外显率达 100%。这种高度可重复的表型提供了第一个研究这种卵巢癌亚型的小鼠模型。从 5 周和 10 周龄突变小鼠的卵巢中分离出的 OSE 细胞表现出特定苗勒氏管上皮标记基因表达的暂时变化，在软琼脂中生长并在受体小鼠中形成异位侵袭性肿瘤，表明细胞发生了转化。基因分析鉴定了突变小鼠肿瘤来源的纯化 OSE 细胞与 WT OSE 细胞相比差异表达的特定 mRNA 和 microRNA。小鼠 OSE 突变体数据集、人类癌细胞系的 Kras 特征和人类卵巢肿瘤阵列数据集之间的转录本或基因映射记录了显着的重叠，表明 KRAS 是这种情况下 OSE 转化的关键驱动因素。这些小鼠中突变 OSE 细胞的两个关键标志是肿瘤抑制因子 Trp53 (p53) 及其 microRNA 靶标 miR-34a-c 的表达升高。我们认为升高的 TRP53 和 miR-34a-c 可能会产生负面调节作用，降低 OSE 细胞的增殖潜力，导致低级别浆液性腺癌表型。
Ovarian cancer is a complex and deadly disease that remains difficult to detect at an early curable stage. Furthermore, although some oncogenic (Kras, Pten/PI3K and Trp53) pathways that are frequently mutated, deleted or amplified in ovarian cancer are known, how these pathways initiate and drive specific morphological phenotypes and tumor outcomes remain unclear. We recently generated Pten fl/fl; KrasG12D;Amhr2-Cre mice to disrupt the Pten gene and express a stable mutant form of KrasG12D in ovarian surface epithelial (OSE) cells. Based on histopathologic criteria, the mutant mice developed low-grade ovarian serous papillary adenocarcinomas at an early age and with 100% penetrance. This highly reproducible phenotype provides the first mouse model in which to study this ovarian cancer subtype. OSE cells isolated from ovaries of mutant mice at 5 and 10 weeks of age exhibit temporal changes in the expression of specific Mullerian epithelial marker genes, grow in soft agar and develop ectopic invasive tumors in recipient mice, indicating that the cells are transformed. Gene profiling identified specific mRNAs and microRNAs differentially expressed in purified OSE cells derived from tumors of the mutant mice compared to WT OSE cells. Mapping of transcripts or genes between the mouse OSE mutant datasets, the Kras signature from human cancer cell lines and the human ovarian tumor array datasets, documented significant overlap, indicating that KRAS is a key driver of OSE transformation in this context. Two key hallmarks of the mutant OSE cells in these mice are the elevated expression of the tumor suppressorsTrp53 (p53) and its microRNA target, miR-34a-c. We propose that elevated TRP53 and miR-34a-c may exert negatively regulatory effects that reduce the proliferative potential of OSE cells leading to the low-grade serous adenocarcinoma phenotype.
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影响因子：
3.7
作者：
Clark-Knowles KV;Senterman MK;Collins O;Vanderhyden BC
通讯作者：
Vanderhyden BC
DOI：
10.1038/nrc2644
发表时间：
2009-06
期刊：
Nature reviews. Cancer
影响因子：
--
作者：
通讯作者：
--
DOI：
10.1126/science.1171396
发表时间：
2009-05-15
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Fan HY;Liu Z;Shimada M;Sterneck E;Johnson PF;Hedrick SM;Richards JS
通讯作者：
Richards JS
影响因子：
82.9
作者：
Dinulescu, DM;Ince, TA;Jacks, T
通讯作者：
Jacks, T
影响因子：
4.6
作者：
Cho, Kathleen R.
通讯作者：
Cho, Kathleen R.