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-4rα^ΔIEC) 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.

中文翻译：

---

Stat6的缺失会影响肠道上皮细胞中的染色质凝聚，从而在与炎症相关和偶发的结肠癌发生的小鼠模型中产生多种结果。

尽管在结直肠癌的遗传学基础上已经取得了很大的进步，但是在其发病过程中细胞间通讯和细胞因子诱导的信号转导的复杂作用仍然鲜为人知。信号转导和转录激活因子6（Stat6）是白介素4（IL-4）信号传导的主要转录因子，并且已经报道了其参与各种肿瘤类型的发展。在这里，我们旨在检查Stat6在肠癌发生小鼠模型中肠上皮细胞（IEC）中的作用。野生型（WT），Stat6基因敲除（Stat6 ^-/-）和肠上皮细胞特异性IL-4Rα基因敲除（Il- ^4rαΔIEC小鼠经历了与结肠炎相关的（AOM / DSS）和与结肠炎无关的（偶发性）致癌作用。通过免疫组织化学，免疫印迹和RT-PCR分析评估IEC增殖，凋亡和RNA表达。我们发现Stat6 ^-/-小鼠在结肠炎相关的致癌模型中发展出更多的肿瘤。这伴随着结肠炎期间更明显的炎症反应以及IEC Stat3依赖性增殖的升高。由于Stat6缺乏导致独立于IL-4Rα参与的烷基化剂处理，Stat6缺乏导致IEC中DNA损伤反应的增加，染色质紧实度增加，从而增加了DSS诱发结肠炎敏感性的增加，这是由于初始致癌物暴露引起的细胞死亡增加所致。因此，Stat6的缺失会导致更严重的结肠炎和增加的肿瘤负荷，但是启动Stat6的缺失^-/-IEC在没有明显炎症的情况下防止了肿瘤的形成。我们的数据揭示了Stat6在肠上皮细胞染色质压实中出乎意料的IL-4独立功能，最终在不同的肠肿瘤发生模型中提供了肿瘤抑制作用和肿瘤促进作用。