@article{2792fbd1671a4130a265d7ee9d48bbf1,
title = "Tumour resistance in induced pluripotent stem cells derived from naked mole-rats",
abstract = "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.",
author = "Shingo Miyawaki and Yoshimi Kawamura and Yuki Oiwa and Atsushi Shimizu and Tsuyoshi Hachiya and Hidemasa Bono and Ikuko Koya and Yohei Okada and Tokuhiro Kimura and Yoshihiro Tsuchiya and Sadafumi Suzuki and Nobuyuki Onishi and Naoko Kuzumaki and Yumi Matsuzaki and Minoru Narita and Eiji Ikeda and Kazuo Okanoya and Seino, {Ken Ichiro} and Hideyuki Saya and Hideyuki Okano and Kyoko Miura",
note = "Funding Information: We thank Drs D. Sipp for proofreading the manuscript; J. Kohyama, A. Takaoka and professors at the Institute for Genetic Medicine Hokkaido University for their administrative support and scientific discussion; N. Arai, C. Fukaya, Y. Tanabe and Y. Fujimura for help with animal maintenance; S. Osuka and all members of the H.O. and K.M. laboratories for technical assistance and scientific discussion; S. Yamanaka, K. Okita and K. Takahashi for 20D17-, 38C2 Nanog-EGFP Ms-iPSCs and 201B7 human-iPSCs; K. Niibe for N3E6 Ms-iPSCs; M. Ikawa and M. Okabe for EGR-G101 ESCs; H. Miyoshi for lentiviral vectors; T. Kitamura for PLAT-E and pMXs retroviral vectors; J. Miyazaki for pCAGGS-hLIF vectors; H. Naka-Kaneda for pCSII-EF-RfA-TKhyg vector. This work was supported in part by PRESTO of the Japan Science and Technology Agency to K.M.; Grants-in-Aid for Scientific Research from the Japanese Society for the Promotion of Science from the Ministry of Education, Culture, Sports, Science and Technology (MEXT) to K.M. and Y.K.; Grant-in-Aid for Scientific Research on Innovative Areas 'Oxygen Biology: a new criterion for integrated understanding of life' from the MEXT to K.M.; and the Funding Program for World-Leading Innovative R&D on Science and Technology (FIRST Program) to H.O. K.M. was supported by the Takeda Science Foundation, Mitsubishi Foundation, Japan Foundation For Aging And Health, Sekisui Chemical Innovations Inspired by Nature Research Support Program, Astellas Foundation for Research on Metabolic Disorders and Mochida Memorial Foundation for Medical and Pharmaceutical Research. K.M. and S.M. were Research Fellows of the Japanese Society for the Promotion of Science.",
year = "2016",
month = may,
day = "10",
doi = "10.1038/ncomms11471",
language = "English",
volume = "7",
journal = "Nature Communications",
issn = "2041-1723",
publisher = "Nature Publishing Group",
}
