Pla2g2a, Runx1 and Colorectal Cancer Risk

描述（由申请人提供）： 结直肠癌（CRC）是西方世界癌症死亡的第二大原因。影响CRC风险的遗传因素的鉴定可用于表征CRC发展的分子机制，并预测个体的CRC风险。哺乳动物肠道的上皮和基质区室之间的信号传导对于维持肠道稳态和预防疾病如炎症和癌症是必不可少的。我们以前的研究主要集中在分泌型磷脂酶A2基因Pla 2g 2a上，该基因已被鉴定为肠癌的易感基因。重要的是，Pla 2g 2a不是以细胞自主方式起作用的“经典”癌基因或肿瘤抑制基因，而是影响上皮-间质相互作用，可能通过调节炎症反应。我们已经证明Pla 2g 2a除了在ApcMin/+小鼠和AOM致癌物诱导的结肠肿瘤发展模型中的肿瘤抑制作用之外，还使用各种小鼠模型（Muc 2缺陷、IL-10缺陷）赋予对炎症诱导的结肠癌的抗性。通过比较Pla 2g 2a-“敲除”和Pla 2g 2a-转基因小鼠的健康（非肿瘤性）结肠的全基因组表达谱来表征Pla 2g 2a的作用，证实了其对炎症的作用，并揭示Runx 1是其主要靶点。由于Runx 1在造血细胞（如Foxp 3阳性调节性T细胞（TR））的分化中起着关键作用，这些数据意味着结肠癌的遗传易感性受到介导肠道免疫稳态的因素的影响。本申请的中心假设是Runx 1是肠癌的抑制因子，其活性受Pla 2g 2a调节，并且Runx 1的表达是小鼠模型中Pla 2g 2a的肿瘤抗性的基础。我们的总体长期目标是通过表征上皮-基质相互作用介导肠道免疫稳态和调节结肠肿瘤发展的机制来降低CRC死亡率。这里提出的具体研究的目标是结肠肿瘤发展的病理特征，由决定肠道稳态的上皮或基质免疫细胞的遗传修饰启动，特别是通过利用Pla 2g 2a转基因和Runx 1条件性敲除小鼠。

DESCRIPTION (provided by applicant): Colorectal cancer (CRC) is the second leading cause of cancer deaths in the western world. Identification of genetic factors that influence CRC risk can be used to characterize the molecular mechanisms underlying CRC development, and to predict an individual's CRC risk. Signaling between the epithelial and stromal compartments of the mammalian intestine is essential for maintenance of gut homeostasis and the prevention of diseases such as inflammation and cancer. Our previous studies have focused on the secretory phospholipase A2 gene Pla2g2a, which has been identified as a susceptibility gene for intestinal cancer. Importantly, Pla2g2a is not a `classical' oncogene or tumor suppressor gene that functions in a cell-autonomous manner, but rather affects epithelial - stroma interactions, probably through modulation of inflammatory responses. We have demonstrated that Pla2g2a confers resistance to inflammation-induced colon cancer using various mouse models (Muc2-deficiency, IL-10-deficiency), in addition to its tumor suppressive effects in ApcMin/+ mice and in an AOM carcinogen-induced model of colon tumor development. Characterization of the effects of Pla2g2a by comparison of genome-wide expression profiles from healthy (non-neoplastic) colon of Pla2g2a- `knockout' and Pla2g2a-transgenic mice confirmed its effects on inflammation, and revealed Runx1 as its major target. As Runx1 plays a key role in differentiation of hematopoietic cells, such as Foxp3-positive regulatory T cells (TR), these data imply that genetic predisposition to colon cancer is influenced by factors that mediate gut immune homeostasis. The central hypothesis of this application is that Runx1 is a suppressor of intestinal cancer whose activity is regulated by Pla2g2a, and that expression of Runx1 underlies the tumor resistance of Pla2g2a in mouse models. Our general, long-term objectives are to reduce CRC mortality rates by characterizing the mechanisms through which epithelial - stroma interactions mediate gut immune homeostasis and modulate colon tumor development. The goal of the specific research proposed here is the pathologic characterization of colon tumor development, initiated by genetic modification of epithelial or stromal immune cells that determine gut homeostasis, in particular by making use of Pla2g2a-transgenic and Runx1-conditional-knockout mice.