Abstract
While great advances have been achieved regarding the genetic basis of colorectal cancer, the complex role of cell–cell communication and cytokine-induced signaling during its pathogenesis remains less understood. Signal transducer and activator of transcription 6 (Stat6) is the main transcription factor of interleukin-4 (IL-4) signaling and its participation in the development of various tumor types has been already reported. Here we aimed to examine the contribution of Stat6 in intestinal epithelial cells (IEC) in mouse models of intestinal carcinogenesis. Wild-type (WT), Stat6 knockout (Stat6−/−), and intestinal epithelial cell-specific IL-4Rα knockout (Il-4rαΔIEC) mice were subjected to colitis-associated (AOM/DSS) and colitis-independent (sporadic) carcinogenesis. IEC proliferation, apoptosis and RNA expression were evaluated by immunohistochemical, immunoblot, and RT-PCR analysis. We found that Stat6−/− mice developed more tumors in the colitis-associated carcinogenesis model. This was accompanied by a more pronounced inflammatory response during colitis and an elevated Stat3-dependent proliferation of IEC. Increased sensitivity to DSS-induced colitis was caused by elevated cell death in response to the initial carcinogen exposure as Stat6 deficiency led to increased chromatin compaction affecting DNA damage response in IEC upon treatment with alkylating agents independently of IL-4Rα engagement. Thus, loss of Stat6 caused more severe colitis and increased tumor load, however loss-of-initiated Stat6−/− IEC prevented tumor formation in the absence of overt inflammation. Our data unravel unexpected IL-4-independent functions of Stat6 in chromatin compaction in intestinal epithelial cells ultimately providing both tumor suppressive as well as tumor promoting effects in different models of intestinal tumorigenesis.
Highlights
Electronic supplementary material The online version of this article contains supplementary material, which is available to authorized users.In spite of the remarkable clinical advances in cancer diagnosis and treatment achieved in the last decades, colorectal cancer continues to be an important cause of mortality worldwide with ~700,000 deaths reported yearly [1]
Considering Signal transducer and activator of transcription 6 (Stat6) the main transcription factor downstream of IL-4 receptor engagement, which has been associated with M2 macrophage polarization [21], we aimed to evaluate in Stat6-deficient inflamed mucosa the expression of genes typically expressed upon M2 polarization
A considerable amount of data endorses the concept that Stat6 is critical to mediate transcriptional activation upon IL-4 and IL-13 stimulation, emphasizing the important canonical IL-4/IL-13 dependent functions of Stat6 in immune cells [11,12,13]
Summary
Signaling induced by the tumor microenvironment controlling cell fate decisions as well as polarization of inflammatory immune cells play an important role during all stages of tumorigenesis [2]. Expression of the type I receptor is restricted to immune cells while the type II receptor is found in other cell types, including epithelial cells [5,6,7,8,9,10] Both IL-4 and IL-13 induce JAKdependent tyrosine phosphorylation of the receptor and subsequent STAT6 phosphorylation. In an IL-4-dependent manner Stat has been suggested to promote colorectal cancer due to its ability to polarize myeloid cells in a wound–healing/tumorpromoting alternative phenotype, which differentiates these cells from the tumor-suppressing IFNγ-mediated classical activation phenotype [18]. Whether Stat in intestinal epithelial cells can directly contribute to colon carcinogenesis has not been fully addressed yet
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