Department of Radiation Oncology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
Department of Medicine, University of Illinois at Chicago, Chicago, IL, USA.
Sci Rep. 2018 Nov 7;8(1):16501. doi: 10.1038/s41598-018-34792-y.
Mice lacking Sirt2 spontaneously develop tumors in multiple organs, as well as when expressed in combination with oncogenic Kras, 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 pancreas of Sirt2 mice display active inflammation, whereas wild-type mice had mostly recovered. In addition, the pancreas from the Sirt2 mice exhibited extensive tissue fibrosis, which was still present at six weeks after exposure. The mice lacking Sirt2 also 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 Kras mutations was observed in the Sirt2 mice that is enhanced in the recovering pancreas after exposure to caerulein. Finally, transcriptome analysis of the pancreas of 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 injury and induced an inflammatory phenotype permissive for the accumulation of cells carrying oncogenic Kras mutations.
缺乏 Sirt2 的小鼠会自发地在多个器官中形成肿瘤，并且当与致癌性 Kras 表达结合时，会导致胰腺肿瘤。在这里，我们报告说，在 caerulein 诱导的胰腺炎后，缺乏 Sirt2 的小鼠表现出增强的炎症表型和延迟的胰腺组织恢复。损伤后 7 天，Sirt2 缺陷型小鼠的胰腺显示出活跃的炎症，而野生型小鼠的胰腺已经大部分恢复。此外，Sirt2 缺陷型小鼠的胰腺还表现出广泛的组织纤维化，这种纤维化在暴露后 6 周仍然存在。缺乏 Sirt2 的小鼠还表现出增强的全身性促炎表型，这种表型随着年龄的增长而变得更加明显。重要的是，在暴露于 caerulein 后恢复的胰腺中，观察到 Sirt2 小鼠中自发发生致癌性 Kras 突变的细胞群体积累增加。最后，对 Sirt2 小鼠胰腺的转录组分析显示出促炎的基因组特征。这些结果表明，Sirt2 的缺失以及年龄的增加增强了对胰腺损伤的免疫反应，并诱导了有利于携带致癌性 Kras 突变的细胞积累的炎症表型。
