Abundant Nucleostemin Expression Supports the Undifferentiated Properties of Germ Cell Tumors
Abundant Nucleostemin Expression Supports the Undifferentiated Properties of Germ Cell Tumors
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DOI：
10.1016/j.ajpath.2013.04.018
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发表时间：
2013-08-01
影响因子：
6
通讯作者：
Hirao, Atsushi
中科院分区：
文献类型：
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作者：
Uema, Noriyuki;Ooshio, Takako;Hirao, Atsushi
核干蛋白是一种核仁gtp结合蛋白，参与核糖体的生物发生和端粒的保护。我们研究了NS在人生殖细胞肿瘤中的表达及其在小鼠生殖细胞肿瘤模型中的作用。NS在未分化或未分化的人睾丸生殖细胞肿瘤中大量表达。NS与OCT3/4同时表达，OCT3/4是原始生殖细胞和胚胎癌中多能干细胞未分化状态的关键调节因子。为了研究NS在体内肿瘤生长中的作用，我们采用小鼠畸胎瘤模型。对NS启动子驱动GFP表达的胚胎干细胞畸胎瘤的分析表明，高表达NS的细胞增殖活跃，并表现出肿瘤启动细胞的特征，包括在体内启动和繁殖肿瘤细胞的能力。表达ns的细胞比不表达ns的细胞表现出更高的GTP水平。由于NS蛋白被胞内GTP稳定，代谢变化可能有助于在未分化细胞中丰富的NS表达。畸胎瘤中OCT3/4缺失导致NS表达缺失，导致生长迟缓。最后，我们发现缺乏NS的畸胎瘤失去了其未分化特征，导致肿瘤增殖缺陷。这些数据表明，NS的大量表达支持生殖细胞肿瘤的未分化特性。
Nucleostemin (NS) is a nucleolar GTP-binding protein that is involved in ribosomal biogenesis and protection of telomeres. We investigated the expression of NS in human germ cell tumors and its function in a mouse germ cell tumor model. NS was abundantly expressed in undifferentiated, but not differentiated, types of human testicular germ cell tumors. NS was expressed concomitantly with OCT3/4, a critical regulator of the undifferentiated status of pluripotent stem cells in primordial germ cells and embryonal carcinomas. To investigate the rotes of NS in tumor growth in vivo, we used a mouse teratoma model. Analysis of teratomas derived from embryonic stem cells in which the NS promoter drives GFP expression showed that cells highly expressing NS were actively proliferating and exhibited the characteristics of tumor-initiating cells, including the ability to initiate and propagate tumor cells in vivo. NS-expressing cells exhibited higher Levels of GTP than non-NS-expressing cells. Because NS protein is stabilized by intracellular GTP, metabolic changes may contribute to abundant NS expression in the undifferentiated cells. OCT3/4 deficiency in teratomas led to loss of NS expression, resulting in growth retardation. Finally, we found that teratomas deficient in NS lost their undifferentiated characteristics, resulting in defective tumor proliferation. These data indicate that abundant expression of NS supports the undifferentiated properties of germ cell tumors.