期刊
COMMUNICATIONS BIOLOGY
卷 5, 期 1, 页码 -出版社
NATURE PORTFOLIO
DOI: 10.1038/s42003-022-03241-y
关键词
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资金
- AMED [JP21bm0704040, JP21gm5010001]
- JSPS KAKENHI [JP21H02392, JP21H05143, JP19K22370, JP18H02365, JP16H06279, JP19K06469, JP16K07079, JP25430116, JP18K14601, JP9J00641, JP16H06276]
- Tenure-Track Grant of Kumamoto University
- Takeda Science Foundation
- KOSE Cosmetology Research Foundation
- Kanzawa Medical Research Foundation
- Nakatomi Foundation
- Naito Foundation
- Foundation for Promotion of Cancer Research
- Kato Memorial Bioscience Foundation
- MSD Life Science Foundation
- ROIS-DS-JOINT [012RP2018]
- Inamori Foundation
- SGH Foundation
- Ichiro Kanehara Foundation
- Terumo Lifes Science Foundation
- Frontier Salon Foundation
- World Premier International Research Center Initiative (WPI), MEXT, Japan
Naked mole-rats exhibit resistance to cancer through a dampened inflammatory response. The study found that immune cell infiltration in the skin of naked mole-rats was significantly lower compared to mice after carcinogenic insults. The mole-rats carry mutations in two necroptosis-related genes, which may contribute to their enhanced cancer resistance.
Naked mole-rats (NMRs) have a very low spontaneous carcinogenesis rate, which has prompted studies on the responsible mechanisms to provide clues for human cancer prevention. However, it remains unknown whether and how NMR tissues respond to experimental carcinogenesis induction. Here, we show that NMRs exhibit extraordinary resistance against potent chemical carcinogenesis induction through a dampened inflammatory response. Although carcinogenic insults damaged skin cells of both NMRs and mice, NMR skin showed markedly lower immune cell infiltration. NMRs harbour loss-of-function mutations in RIPK3 and MLKL genes, which are essential for necroptosis, a type of necrotic cell death that activates strong inflammation. In mice, disruption of Ripk3 reduced immune cell infiltration and delayed carcinogenesis. Therefore, necroptosis deficiency may serve as a cancer resistance mechanism via attenuating the inflammatory response in NMRs. Our study sheds light on the importance of a dampened inflammatory response as a non-cell-autonomous cancer resistance mechanism in NMRs. Naked mole rats are found to be resistant to cancer development through dampened inflammatory response due to genetically determined impaired necroptosis, with essential necroptosis genes RIPK3 and MLKL containing mutations causing premature stop codons.
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