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.
Highlights
The naked mole-rat (NMR, Heterocephalus glaber), which is the longest-lived rodent species, exhibits extraordinary resistance to cancer
We generate NMR-Induced pluripotent stem cells (iPSCs) and show that they do not exhibit teratoma-forming tumorigenicity. We demonstrate that this phenotype is the result of the activation of a tumour-suppressor alternative reading frame (ARF), which is strongly suppressed in Ms-iPSCs13–15, and a unique frameshift mutation in ES cell-expressed Ras (ERAS), which positively regulates the tumorigenicity of Ms-ESCs16
Given the results of the present study, we suggest that NMR-specific ARF suppression-induced senescence (ASIS) may act as a second safeguard, inducing cellular senescence when ARF is suppressed in cells, in which ARF has been derepressed by exposure to stressors (Fig. 4k)
Summary
The naked mole-rat (NMR, Heterocephalus glaber), which is the longest-lived rodent species, exhibits extraordinary resistance to cancer. 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 expression of many tumour suppressors, oncogenes and pluripotency genes, including Oct[4], Sox[2], Klf[4] and c-Myc (OSKM), contributes to both reprogramming and oncogenesis[5,11], and the transient in vivo expression of OSKM has been shown to induce tumours in certain tissues[12] These observations raise the question of whether somatic cell reprogramming conferring pluripotency and tumorigenicity can be induced in cancer-resistant animals, such as the naked mole-rat. This study provides novel insights into NMR cancer resistance and methods for generating safe iPSCs
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