Hes1-loss promotes dysregulation of epithelial homeostasis and inflammation in a serrated adenocarcinoma model

与传统的腺瘤-癌途径不同，“锯齿状” 途径“是假设的一种分子途径，适用于从 一些锯齿状的前驱病变。此外，炎症是一个已知的风险因素， CRC。然而，锯齿状病变的分子致癌机制 转化，通常与慢性炎症有关，仍然是一种 重要的知识鸿沟。以前我们发现Notch/HES1的表达在 大多数人无柄锯齿状腺瘤和右侧结直肠癌，是一种普遍存在的标记 用于IBD相关锯齿状病变和结直肠癌。此外，Notch/Hes1-亏损是基础 锯齿状结肠炎相关性结直肠癌动物模型的肠道病理学研究 损伤。在本提案中，我们将结合使用多种方法(有机培养、 人SSA和锯齿状CRC的分子和细胞信号网络分析 微生物组深度基因测序等)和我们独特的无致癌物动物模型 研究HES1缺失破坏上皮细胞动态平衡的机制，以及 确定这一过程如何与促肿瘤细胞因子环境合作 以白介素1β为代表的促癌变作用。

Distinct from the conventional adenoma–carcinoma pathway, the “serrated pathway” is a molecular pathway postulated for a subset of CRCs that develop from some serrated precursor lesions. In addition, inflammation is a known risk factor for CRC. However, molecular carcinogenic mechanism driving serrated lesion transformation, which is frequently associated with chronic inflammation, remains an important knowledge gap. Previously we found that Notch/HES1 expression is lost in most human sessile serrated adenoma and right-sided CRC, and is a ubiquitous marker for IBD-associated serrated lesions and CRC. In addition, Notch/Hes1-loss underlies the gut pathology of an animal model of colitis-associated CRC featuring serrated-like lesions. In this proposal, we will use a combination of approaches (organoid culture, molecular and cellular signaling network analysis of human SSA and serrated CRC, and microbiome deep gene sequencing, etc) and our unique carcinogen-free animal models to study the mechanism by which HES1-loss disrupts epithelial homeostasis, and defining how this process cooperates with a pro-tumorigenic cytokine milieu represented by IL1β to promote carcinogenesis.