Loss of Sirt2 increases and prolongs a caerulein-induced pancreatitis permissive phenotype and induces spontaneous oncogenic Kras mutations in mice
2018
Mice lacking
Sirt2spontaneously develop tumors in multiple organs, as well as when expressed in combination with oncogenic KrasG12D, leading to
pancreatic tumors. Here, we report that after caerulein-induced pancreatitis,
Sirt2-deficient mice exhibited an increased inflammatory phenotype and delayed pancreatic tissue recovery. Seven days post injury, the
pancreasof
Sirt2−/− mice display active inflammation, whereas wild-type mice had mostly recovered. In addition, the
pancreasfrom the
Sirt2−/− mice exhibited extensive tissue fibrosis, which was still present at six weeks after exposure. The mice lacking
Sirt2also demonstrated an enhanced whole body pro-inflammatory phenotype that was most obvious with increasing age. Importantly, an accumulation of a cell population with spontaneous cancerous KrasG12D mutations was observed in the
Sirt2−/− mice that is enhanced in the recovering
pancreasafter exposure to caerulein. Finally, transcriptome analysis of the
pancreasof the
Sirt2−/− mice exhibited a pro-inflammatory
genomic signature. These results suggest that loss of
Sirt2, as well as increased age, enhanced the immune response to
pancreatic injuryand induced an inflammatory phenotype permissive for the accumulation of cells carrying oncogenic Kras mutations.
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