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。识别影响结直肠癌风险的遗传因素可用于表征结直肠癌发生的分子机制，并预测个体的结直肠癌风险。哺乳动物肠道上皮和间质之间的信号传递对于维持肠道内环境平衡和预防炎症和癌症等疾病至关重要。我们以前的研究主要集中在分泌型磷脂酶A2基因Pla2g2a上，该基因已被确定为肠癌的易感基因。重要的是，Pla2g2a不是一个经典的癌基因或肿瘤抑制基因，它以细胞自主的方式发挥作用，而是影响上皮-间质相互作用，可能是通过调节炎症反应。除了在ApcMin/+小鼠和AOM致癌物诱导的结肠癌发展模型中的肿瘤抑制作用外，我们还通过各种小鼠模型(Muc2缺乏、IL-10缺乏)证明了Pla2g2a对炎症诱导的结肠癌具有抵抗力。通过比较Pla2g2a-‘基因敲除’和Pla2g2a-转基因小鼠健康(非肿瘤)结肠的全基因组表达谱来表征Pla2g2a的作用，证实了其抗炎作用，并揭示了RUNX1是其主要靶点。由于RUNX1在造血细胞的分化中起关键作用，如Foxp3阳性的调节性T细胞(TR)，这些数据表明结肠癌的遗传易感性受到调节肠道免疫稳态的因素的影响。这一应用的中心假设是RUNX1是一种肠癌抑制因子，其活性受Pla2g2a调节，在小鼠模型中，RUNX1的表达是Pla2g2a抵抗肿瘤的基础。我们的总体和长期目标是通过确定上皮-间质相互作用调节肠道免疫稳态和调节结肠肿瘤发展的机制来降低结直肠癌死亡率。本文提出的具体研究目标是结肠肿瘤发展的病理学特征，由决定肠道动态平衡的上皮或间质免疫细胞的遗传修饰启动，特别是通过利用Pla2g2a转基因和RUNX1条件基因敲除小鼠。

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.