Abstract

Interleukin 4 (IL-4) signaling has been implicated in tumorigenesis in many types of malignancies including breast, lung, brain, renal and pancreatic cancer through different cell-intrinsic mechanisms. In order to understand how IL-4 signaling might affect inflammation-dependent colorectal tumor development and progression, this study aimed to investigate the most prominent components of this pathway: (i) interleukin 4 receptor alpha (IL-4Rα) and (ii) signal transducer and activator of transcription 6 (STAT6). Taking advantage of genetically modified mice and a well-established colitis-associated cancer model functional relevance of IL-4Rα and STAT6 in intestinal epithelial cells was evaluated. Employing the AOM/DSS tumor model mice with global deletion of IL-4Rα developed fewer and smaller colonic tumors than WT mice. Additionally, IL-4Rα loss during colitis-associated tumorigenesis reduced STAT3 activity in transformed colonocytes causing cell cycle arrest at G2-phase due to decreased CYCLIN B1 and CYCLIN E expression. Knowing that STAT6 is crucial to provide gene activation signals in the IL-4 pathway it was expected that Stat6 ablation during colitis-associated tumorigenesis would generate similar results as the ones obtained with IL-4Rα . Surprisingly, Stat6 deficient animals showed enhanced susceptibility to chemically induced intestinal epithelial damage and subsequent colonic inflammation. A significant increase in tumor load and tumor size was observed in these animals followed by an increased STAT3 activation in tumors. STAT3 is known to influence colon cancer development and its compensatory upregulation could explain the phenotype observed in Stat6 knockout mice. The findings here add further insights on STAT6 and IL-4Rα signaling during intestinal tumorigenesis and stress that the loss of a single pathway component can exert dramatic influences for the phenotype of genetically modified mice and for the therapeutical use of inhibitors of signaling pathways. Moreover, considering that STAT6 is the most important known transcription factor downstream of IL-4 these data highlight unexpected IL-4-independent functions of STAT6.