创作:沈志勋 审核:沈志勋 03月12日
  • 饮食诱导的肥胖小鼠中,肠道上皮细胞(IEC)的胰岛素敏感性受损;
  • IEC特异性缺失胰岛素及胰岛素样生长因子1(IGF1)的小鼠表现出肠道屏障功能修复受损,并促进了结肠炎相关癌症(CAC)的发展;
  • 抑制胰岛素信号可使转录因子FOXO1留在细胞核内,从而抑制Dsc3的表达,导致细胞桥粒形成受损,损伤上皮屏障的完整性;
  • IEC特异性的核FoxO1ADA表达及IEC特异性的Dsc3缺失均可损伤肠道屏障完整性并增加CAC负荷。

Intestinal insulin/IGF1 signalling through FoxO1 regulates epithelial integrity and susceptibility to colon cancer



03-04, Article

Abstract & Authors:展开

Obesity promotes the development of insulin resistance and increases the incidence of colitis-associated cancer (CAC), but whether a blunted insulin action specifically in intestinal epithelial cells (IECs) affects CAC is unknown. Here, we show that obesity impairs insulin sensitivity in IECs and that mice with IEC-specific inactivation of the insulin and IGF1 receptors exhibit enhanced CAC development as a consequence of impaired restoration of gut barrier function. Blunted insulin signalling retains the transcription factor FOXO1 in the nucleus to inhibit expression of Dsc3, thereby impairing desmosome formation and epithelial integrity. Both IEC-specific nuclear FoxO1ADA expression and IEC-specific Dsc3 inactivation recapitulate the impaired intestinal integrity and increased CAC burden. Spontaneous colonic tumour formation and compromised intestinal integrity are also observed upon IEC-specific coexpression of FoxO1ADA and a stable Myc variant, thus suggesting a molecular mechanism through which impaired insulin action and nuclear FOXO1 in IECs promotes CAC.

First Authors:
A L Ostermann

Correspondence Authors:
F T Wunderlich

All Authors:
A L Ostermann,C M Wunderlich,L Schneiders,M C Vogt,M A Woeste,B F Belgardt,C M Niessen,B Martiny,A C Schauss,P Frommolt,A Nikolaev,N Hövelmeyer,R C Sears,P J Koch,D Günzel,J C Brüning,F T Wunderlich