PDF(Pubmed)
Abstract：
The mucosal barrier is crucial for intestinal homeostasis, and goblet cells are essential for maintaining the mucosal barrier integrity. The proviral integration site for Moloney murine leukemia virus-1 (PIM1) kinase regulates multiple cellular functions, but its role in intestinal homeostasis during colitis is unknown. Here, we demonstrate that PIM1 is prominently elevated in the colonic epithelia of both ulcerative colitis patients and murine models, in the presence of intestinal microbiota. Epithelial PIM1 leads to decreased goblet cells, thus impairing resistance to colitis and colitis-associated colorectal cancer (CAC) in mice. Mechanistically, PIM1 modulates goblet cell differentiation through the Wnt and Notch signaling pathways. Interestingly, PIM1 interacts with histone deacetylase 2 (HDAC2) and downregulates its level via phosphorylation, thereby altering the epigenetic profiles of Wnt signaling pathway genes. Collectively, these findings investigate the unknown function of the PIM1-HDAC2 axis in goblet cell differentiation and ulcerative colitis/CAC pathogenesis, which points to the potential for PIM1-targeted therapies of ulcerative colitis and CAC.
摘要：
粘膜屏障对肠道稳态至关重要，杯状细胞是维持粘膜屏障完整性所必需的。莫洛尼鼠白血病病毒1（PIM1）激酶的前病毒整合位点调节多种细胞功能，但其在结肠炎期间的肠道稳态中的作用尚不清楚。这里,我们证明，PIM1在溃疡性结肠炎患者和小鼠模型的结肠上皮中显著升高，在肠道微生物群的存在。上皮PIM1导致杯状细胞减少，从而损害小鼠对结肠炎和结肠炎相关性结直肠癌（CAC）的抵抗力。机械上,PIM1通过Wnt和Notch信号通路调节杯状细胞分化。有趣的是,PIM1与组蛋白脱乙酰酶2（HDAC2）相互作用，并通过磷酸化下调其水平，从而改变Wnt信号通路基因的表观遗传谱。总的来说，这些发现探讨了PIM1-HDAC2轴在杯状细胞分化和溃疡性结肠炎/CAC发病机制中的未知功能，这表明PIM1靶向治疗溃疡性结肠炎和CAC的潜力。
