Tumour resistance in induced pluripotent stem cells derived from naked mole-rats

Shingo Miyawaki, Yoshimi Kawamura, Yuki Oiwa, Atsushi Shimizu, Tsuyoshi Hachiya, Hidemasa Bono, Ikuko Koya, Yohei Okada, Tokuhiro Kimura, Yoshihiro Tsuchiya, Sadafumi Suzuki, Nobuyuki Onishi, Naoko Kuzumaki, Yumi Matsuzaki, Minoru Narita, Eiji Ikeda, Kazuo Okanoya, Ken-ichiro Seino, Hideyuki Saya, Hideyuki Okano () and Kyoko Miura ()
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Shingo Miyawaki: Biomedical Animal Research Laboratory, Institute for Genetic Medicine, Hokkaido University
Yoshimi Kawamura: Biomedical Animal Research Laboratory, Institute for Genetic Medicine, Hokkaido University
Yuki Oiwa: Biomedical Animal Research Laboratory, Institute for Genetic Medicine, Hokkaido University
Atsushi Shimizu: Iwate Tohoku Medical Megabank Organization, Disaster Reconstruction Center, Iwate Medical University
Tsuyoshi Hachiya: Iwate Tohoku Medical Megabank Organization, Disaster Reconstruction Center, Iwate Medical University
Hidemasa Bono: Database Center for Life Science, Research Organization of Information and Systems
Ikuko Koya: Keio University School of Medicine
Yohei Okada: Keio University School of Medicine
Tokuhiro Kimura: Yamaguchi University Graduate School of Medicine
Yoshihiro Tsuchiya: Hoshi University School of Pharmacy and Pharmaceutical Sciences
Sadafumi Suzuki: Keio University School of Medicine
Nobuyuki Onishi: Institute for Advanced Medical Research, Keio University School of Medicine
Naoko Kuzumaki: Keio University School of Medicine
Yumi Matsuzaki: Shimane University Faculty of Medicine
Minoru Narita: Hoshi University School of Pharmacy and Pharmaceutical Sciences
Eiji Ikeda: Yamaguchi University Graduate School of Medicine
Kazuo Okanoya: Graduate School of Arts and Science, The University of Tokyo
Ken-ichiro Seino: Institute for Genetic Medicine, Hokkaido University
Hideyuki Saya: Institute for Advanced Medical Research, Keio University School of Medicine
Hideyuki Okano: Keio University School of Medicine
Kyoko Miura: Biomedical Animal Research Laboratory, Institute for Genetic Medicine, Hokkaido University

Nature Communications, 2016, vol. 7, issue 1, 1-9

Abstract: 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.

Date: 2016
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DOI: 10.1038/ncomms11471

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