Transcriptomics Analysis of Nrf2 Regulators in Cancer Resistant and Long-Lived Naked Mole-Rats

Abstract

ABSTRACT Purpose: Naked mole-rats (NMR, Heterocephalus glaber) have extreme resistance to cancer although they are known as the longest-living rodent with their 30-year maximum lifespan. Therefore, NMRs have rapidly emerged as a natural model for biomedical research. Studies have shown that NMRs can better tolerate stress due to mechanisms, such as upregulation of the Nrf2 pathway. Another mechanism proposed to contribute to their protection from stress involves stem cells. Therefore, in this study, we aimed to identify the regulation of Nrf2 signaling in NMR fibroblasts and induced pluripotent stem cells (iPSCs). Methods: The transcriptomics data of NMR and laboratory mice (Mus musculus) were used in the study. Particularly, the genes that are accepted as Nrf2 activators (Dpp3, Sqstm1, Palb2, Amer1, Mapk14, Trp53) and inhibitors (Keap1, Siah1, Btrc) were comparatively analyzed in fibroblasts and iPSCs of both species. Results: Our data demonstrated differentially expressed gene expressions between different cell types. Among target Nrf2 activators, Palb2 RNA expression was found to be increased significantly (p<0.0001) in NMR fibroblasts when compared to mouse fibroblasts. In addition, the expression of Palb2 was even more increased in NMR iPSCs when compared to NMR fibroblasts (p<0.0001). Conclusion: It was shown, for the first time, Palb2 could be partially responsible for the activation of Nrf2 pathway. These results contribute to literature on the stress resistance of the NMRs and its relationship with their superior features of aging and cancer.