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.
authors.affiliation: Biomedical Animal Research Laboratory, Institute for Genetic Medicine, Hokkaido University, Hokkaido 060-0815, Japan.|Department of Physiology, Keio University School of Medicine, Tokyo 160-8582, Japan.|Division of Immunobiology, Institute for Genetic Medicine, Hokkaido University, Hokkaido 060-0815, Japan.
authors.forename: Shingo
authors.initials: S
authors.lastname: Miyawaki
authors.affiliation: Biomedical Animal Research Laboratory, Institute for Genetic Medicine, Hokkaido University, Hokkaido 060-0815, Japan.
authors.forename: Yoshimi
authors.initials: Y
authors.lastname: Kawamura
authors.affiliation: Biomedical Animal Research Laboratory, Institute for Genetic Medicine, Hokkaido University, Hokkaido 060-0815, Japan.|Division of Immunobiology, Institute for Genetic Medicine, Hokkaido University, Hokkaido 060-0815, Japan.
authors.forename: Yuki
authors.initials: Y
authors.lastname: Oiwa
authors.affiliation: Division of Biomedical Information Analysis, Iwate Tohoku Medical Megabank Organization, Disaster Reconstruction Center, Iwate Medical University, Iwate 028-3694, Japan.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Shimizu
authors.affiliation: Division of Biomedical Information Analysis, Iwate Tohoku Medical Megabank Organization, Disaster Reconstruction Center, Iwate Medical University, Iwate 028-3694, Japan.
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Hachiya
authors.affiliation: Database Center for Life Science, Research Organization of Information and Systems, Mishima 411-8540, Japan.
authors.forename: Hidemasa
authors.identifier: 0000-0003-4413-0651
authors.initials: H
authors.lastname: Bono
authors.affiliation: Department of Physiology, Keio University School of Medicine, Tokyo 160-8582, Japan.
authors.forename: Ikuko
authors.initials: I
authors.lastname: Koya
authors.affiliation: Department of Physiology, Keio University School of Medicine, Tokyo 160-8582, Japan.|Department of Neurology, Aichi Medical University School of Medicine, Aichi 480-1195, Japan.
authors.forename: Yohei
authors.initials: Y
authors.lastname: Okada
authors.affiliation: Department of Pathology, Yamaguchi University Graduate School of Medicine, Yamaguchi 755-8505, Japan.
authors.forename: Tokuhiro
authors.initials: T
authors.lastname: Kimura
authors.affiliation: Department of Pharmacology, Hoshi University School of Pharmacy and Pharmaceutical Sciences, Tokyo 142-8501, Japan.
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Tsuchiya
authors.affiliation: Department of Physiology, Keio University School of Medicine, Tokyo 160-8582, Japan.
authors.forename: Sadafumi
authors.initials: S
authors.lastname: Suzuki
authors.affiliation: Division of Gene Regulation, Institute for Advanced Medical Research, Keio University School of Medicine, Tokyo 160-8582, Japan.
authors.forename: Nobuyuki
authors.initials: N
authors.lastname: Onishi
authors.affiliation: Department of Physiology, Keio University School of Medicine, Tokyo 160-8582, Japan.|Department of Pharmacology, Hoshi University School of Pharmacy and Pharmaceutical Sciences, Tokyo 142-8501, Japan.
authors.forename: Naoko
authors.initials: N
authors.lastname: Kuzumaki
authors.affiliation: Department of Life Science, Shimane University Faculty of Medicine, Shimane 693-8501, Japan.
authors.forename: Yumi
authors.initials: Y
authors.lastname: Matsuzaki
authors.affiliation: Department of Pharmacology, Hoshi University School of Pharmacy and Pharmaceutical Sciences, Tokyo 142-8501, Japan.
authors.forename: Minoru
authors.initials: M
authors.lastname: Narita
authors.affiliation: Department of Pathology, Yamaguchi University Graduate School of Medicine, Yamaguchi 755-8505, Japan.
authors.forename: Eiji
authors.initials: E
authors.lastname: Ikeda
authors.affiliation: Graduate School of Arts and Science, The University of Tokyo, Tokyo 153-8902, Japan.
authors.forename: Kazuo
authors.initials: K
authors.lastname: Okanoya
authors.affiliation: Division of Immunobiology, Institute for Genetic Medicine, Hokkaido University, Hokkaido 060-0815, Japan.
authors.forename: Ken-Ichiro
authors.initials: K
authors.lastname: Seino
authors.affiliation: Division of Gene Regulation, Institute for Advanced Medical Research, Keio University School of Medicine, Tokyo 160-8582, Japan.
authors.forename: Hideyuki
authors.identifier: 0000-0001-6610-1902
authors.initials: H
authors.lastname: Saya
authors.affiliation: Department of Physiology, Keio University School of Medicine, Tokyo 160-8582, Japan.
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Okano
authors.affiliation: Biomedical Animal Research Laboratory, Institute for Genetic Medicine, Hokkaido University, Hokkaido 060-0815, Japan.|Department of Physiology, Keio University School of Medicine, Tokyo 160-8582, Japan.|PRESTO, Japan Science and Technology Agency, Saitama 332-0012, Japan.
authors.forename: Kyoko
authors.initials: K
authors.lastname: Miura
mesh_terms: D000818:Animals; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000276:immunology; D065150:Cellular Reprogramming / Q000235:genetics / Q000276:immunology; D016147:Genes, Tumor Suppressor; D057026:Induced Pluripotent Stem Cells / Q000166:cytology / Q000276:immunology* / Q000637:transplantation; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D008819:Mice, Nude; D016513:Mice, SCID; D019577:Mole Rats / Q000235:genetics* / Q000276:immunology*; D009154:Mutation; D015689:Oncogene Protein p21(ras) / Q000235:genetics / Q000276:immunology; D016364:Reading Frames; D013724:Teratoma / Q000235:genetics / Q000276:immunology; D013736:Testicular Neoplasms / Q000235:genetics / Q000276:immunology
chemical_list: D015689:Oncogene Protein p21(ras)