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Nat Commun. 2016 May 10;7:11471. doi: 10.1038/ncomms11471.

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

Author information

1
Biomedical Animal Research Laboratory, Institute for Genetic Medicine, Hokkaido University, Hokkaido 060-0815, Japan.
2
Department of Physiology, Keio University School of Medicine, Tokyo 160-8582, Japan.
3
Division of Immunobiology, Institute for Genetic Medicine, Hokkaido University, Hokkaido 060-0815, Japan.
4
Division of Biomedical Information Analysis, Iwate Tohoku Medical Megabank Organization, Disaster Reconstruction Center, Iwate Medical University, Iwate 028-3694, Japan.
5
Database Center for Life Science, Research Organization of Information and Systems, Mishima 411-8540, Japan.
6
Department of Neurology, Aichi Medical University School of Medicine, Aichi 480-1195, Japan.
7
Department of Pathology, Yamaguchi University Graduate School of Medicine, Yamaguchi 755-8505, Japan.
8
Department of Pharmacology, Hoshi University School of Pharmacy and Pharmaceutical Sciences, Tokyo 142-8501, Japan.
9
Division of Gene Regulation, Institute for Advanced Medical Research, Keio University School of Medicine, Tokyo 160-8582, Japan.
10
Department of Life Science, Shimane University Faculty of Medicine, Shimane 693-8501, Japan.
11
Graduate School of Arts and Science, The University of Tokyo, Tokyo 153-8902, Japan.
12
PRESTO, Japan Science and Technology Agency, Saitama 332-0012, Japan.

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.

PMID:
27161380
PMCID:
PMC4866046
DOI:
10.1038/ncomms11471
[Indexed for MEDLINE]
Free PMC Article

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