Tumour resistance in induced pluripotent stem cells derived from naked mole-rats.
Tumour resistance in induced pluripotent stem cells derived from naked mole-rats.
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DOI：
10.1038/ncomms11471
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发表时间：
2016-05-10
影响因子：
16.6
通讯作者：
Miura K
中科院分区：
文献类型：
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作者：
Miyawaki S;Kawamura Y;Oiwa Y;Shimizu A;Hachiya T;Bono H;Koya I;Okada Y;Kimura T;Tsuchiya Y;Suzuki S;Onishi N;Kuzumaki N;Matsuzaki Y;Narita M;Ikeda E;Okanoya K;Seino K;Saya H;Okano H;Miura K
裸鼹鼠（NMR, Heterocephalus glaber）是最长寿的啮齿动物，对癌症表现出非凡的抵抗力。在这里，我们报道核磁共振体细胞对重编程诱导表现出独特的肿瘤抑制反应。在这项研究中，我们生成了核磁共振诱导的多能干细胞（NMR-iPSCs），并发现由于肿瘤抑制因子替代阅读框（ARF）的物种特异性激活和癌基因ES细胞表达的Ras （ERAS）的破坏突变，NMR-iPSCs不表现出畸胎瘤形成的致瘤性。在小鼠iPSCs中强制表达Arf可显著降低致瘤性。此外，我们确定了一种核磁共振特异性肿瘤抑制表型——ARF抑制诱导衰老（ASIS），这可能保护iPSCs和体细胞免受ARF抑制，从而降低致瘤性。因此，核磁共振特异性的ARF调控和ERAS的破坏调节了核磁共振- ipscs的肿瘤耐药性。我们从NMR-iPSCs的研究中获得的发现为iPSCs的致瘤性和核磁共振的抗癌机制提供了新的见解。裸鼹鼠对癌症表现出非凡的抵抗力。在这里，作者表明，由于裸鼹鼠特异性的arf依赖性肿瘤抑制机制，来自裸鼹鼠的诱导多能干细胞缺乏畸胎瘤形成的致瘤性。
The naked mole-rat (NMR, Heterocephalus glaber), which is the longest-lived rodent species, exhibits extraordinary resistance to cancer. Here we report that NMR somatic cells exhibit a unique tumour-suppressor response to reprogramming induction. In this study, we generate NMR-induced pluripotent stem cells (NMR-iPSCs) and find that NMR-iPSCs do not exhibit teratoma-forming tumorigenicity due to the species-specific activation of tumour-suppressor alternative reading frame (ARF) and a disruption mutation of the oncogene ES cell-expressed Ras (ERAS). The forced expression of Arf in mouse iPSCs markedly reduces tumorigenicity. Furthermore, we identify an NMR-specific tumour-suppression phenotype—ARF suppression-induced senescence (ASIS)—that may protect iPSCs and somatic cells from ARF suppression and, as a consequence, tumorigenicity. Thus, NMR-specific ARF regulation and the disruption of ERAS regulate tumour resistance in NMR-iPSCs. Our findings obtained from studies of NMR-iPSCs provide new insight into the mechanisms of tumorigenicity in iPSCs and cancer resistance in the NMR. The naked mole-rat exhibits an exceptional resistance to cancer. Here, the authors show that induced pluripotent stem cells derived from the naked mole-rat lack teratoma-forming tumorigenicity due to a naked mole-rat-specific ARF-dependent tumour-suppression mechanism.