Cooperation between p53 and the telomere-protecting shelterin component Pot1a in endometrial carcinogenesis.
Cooperation between p53 and the telomere-protecting shelterin component Pot1a in endometrial carcinogenesis.
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DOI：
10.1038/onc.2012.232
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发表时间：
2013-04-25
期刊：
影响因子：
8
通讯作者：
Castrillon, D. H.
中科院分区：
文献类型：
--
作者：
Akbay, E. A.;Pena, C. G.;Ruder, D.;Michel, J. A.;Nakada, Y.;Pathak, S.;Multani, A. S.;Chang, S.;Castrillon, D. H.
II型子宫内膜癌（EMCA）仅占所有EMCA的10%，但占EMCA相关死亡率的40%。先前对人类肿瘤的研究已经表明II型肿瘤与受损的端粒之间存在关联。我们假设缺乏小鼠II型EMCA模型是由于实验室小鼠品系中的端粒非常长。我们以前的研究表明，端粒非常短的端粒缺失小鼠发生了组织学上类似于子宫内膜上皮内癌（EIC）的子宫内膜病变，EIC是公认的II型EMCA的前体。然而，这些小鼠没有发展成浸润性子宫内膜腺癌，而是过早地死于多器官衰竭。在这里，我们模拟关键的端粒磨损条件失活Pot1a，一个组成部分的shelterin复合物，稳定端粒，子宫内膜上皮。Pot1a本身的失活不会刺激子宫内膜癌的发生，也不会导致子宫内膜中可检测到的DNA损伤或凋亡。然而，Pot1a和p53的同时失活导致EIC样病变9个月，与晚代端粒酶缺失小鼠中观察到的病变无法区分。这些病变发展为浸润性子宫内膜腺癌，早在9个月大的动物转移性疾病的100%，15个月。这些肿瘤是低分化的子宫内膜腺癌，具有突出的核小体，类似于人类II型癌症。此外，这些肿瘤是具有双链DNA断裂和端到端端粒融合的非整倍体，并且大多数是四倍体或近四倍体。这些研究进一步支持了端粒不稳定性在II型子宫内膜癌发生中起关键作用的假设，并为最近的研究提供了一个有趣的体内相关性，该研究暗示端粒依赖性四倍化是癌发生的重要机制。
Type II endometrial cancer (EMCA) represents only 10% of all EMCAs, but accounts for 40% of EMCA-related mortality. Previous studies of human tumors have shown an association between Type II tumors and damaged telomeres. We hypothesized that the lack of murine Type II EMCA models is due to the extremely long telomeres in laboratory mouse strains. We previously showed that telomerase-null mice with critically short telomeres developed endometrial lesions histologically resembling endometrial intraepithelial carcinoma (EIC), the accepted precursor for Type II EMCA. However, these mice did not develop invasive endometrial adenocarcinoma, and instead succumbed prematurely to multi-organ failure. Here, we modeled critical telomere attrition by conditionally inactivating Pot1a, a component of the shelterin complex that stabilizes telomeres, within endometrial epithelium. Inactivation of Pot1a by itself did not stimulate endometrial carcinogenesis, and did not result in detectable DNA damage or apoptosis in endometrium. However, simultaneous inactivation of Pot1a and p53 resulted in EIC-like lesions by 9 months indistinguishable from those seen in late generation telomerase-null mice. These lesions progressed to invasive endometrial adenocarcinomas as early as 9 months of age with metastatic disease in 100% of the animals by 15 months. These tumors were poorly differentiated endometrial adenocarcinomas with prominent nuclear atypia, resembling human Type II cancers. Furthermore, these tumors were aneuploid with double-stranded DNA breaks and end-to-end telomere fusions and most were tetraploid or near-tetraploid. These studies lend further support to the hypothesis that telomeric instability has a critical role in Type II endometrial carcinogenesis and provides an intriguing in-vivo correlate to recent studies implicating telomere-dependent tetraploidization as an important mechanism in carcinogenesis.
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DOI：
10.1126/science.1170633
发表时间：
2009-11-13
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
de Lange T
通讯作者：
de Lange T
影响因子：
14.9
作者：
Forbes SA;Bindal N;Bamford S;Cole C;Kok CY;Beare D;Jia M;Shepherd R;Leung K;Menzies A;Teague JW;Campbell PJ;Stratton MR;Futreal PA
通讯作者：
Futreal PA
影响因子：
6
作者：
Akbay, Esra A.;Contreras, Cristina M.;Castrillon, Diego H.
通讯作者：
Castrillon, Diego H.
影响因子：
11.2
作者：
Daikoku T;Hirota Y;Tranguch S;Joshi AR;DeMayo FJ;Lydon JP;Ellenson LH;Dey SK
通讯作者：
Dey SK
影响因子：
64.8
作者：
di Fagagna, FD;Reaper, PM;Jackson, SP
通讯作者：
Jackson, SP