Another Possible Cancer Suppression Mechanism in Naked Mole Rats

Besides living for nine times longer than other, similarly sized rodent species, naked mole rats are also highly resistant to cancer, to the point at which only a handful of cases have ever been observed. The scientific community is seeking the roots of this cancer resistance to see if the mechanisms involved can form the basis for human therapies. So far, research has centered on differences in the biochemistry of tumor suppressor gene p16, and hyaluronan, which may be responsible for activating p16 more aggressively in naked mole rats. Here, researchers identify another possibly relevant difference in mechanisms relating to the tumor suppressor gene ARF; in naked mole-rats, unlike other mammals, disabling this gene causes cells to halt replication and become senescent. This may act to close off a variety of mutational paths to cancer, changes that will spawn tumors in mice, but not in naked mole rats.

The research team took skin fibroblast tissue from adult naked mole-rats and reprogrammed the cells to revert to pluripotent stem cells. These are called induced pluripotent stem cells (iPSCs) and, like embryonic stem cells, are capable of becoming any type of tissue in the body. However, these stem cells can also form tumours called teratomas when transplanted back into the animals. When the naked mole-rats' iPSCs were inserted into the testes of mice with extremely weak immune systems, the team discovered that they didn't form tumours in contrast to human iPSCs and mouse iPSCs. Upon further investigation, they found that a tumour-suppressor gene called alternative reading frame (ARF), which is normally suppressed in mouse and human iPSCs, remained active in the mole-rat iPSCs.

The team also found that ERAS, a tumorigenic gene expressed in mouse embryonic stem cells and iPSCs, was mutated and dysfunctional in the naked mole-rat iPSCs. When the researchers disabled the ARF gene, forced the expression of the mouse ERAS gene in the naked mole-rat iPSCs, and then inserted them into the mice, the mice grew large tumours. When researchers suppressed the ARF gene in naked mole-rat cells during the reprogramming process to iPSCs, the cells stopped proliferation with sign of cellular senescence, while the opposite happens with mouse cells. Researchers theorize that this further helps protect the naked mole-rat by reducing the chance for tumour formation. They call this ARF suppression-induced senescence (ASIS) and it appears to be unique to the naked mole-rat.


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