The role of IL8 in colitis-associated tumor initiation

描述（由申请人提供）：结肠炎相关癌症的发病机制尚不清楚。填补这一知识空白是一项重要挑战，因为如果不进行干预，高达18%的慢性溃疡性结肠炎（UC）患者将发展为结直肠癌。因此，我们的长期目标是通过确定炎症促进慢性溃疡性结肠炎患者恶性转化的机制来制定CAC的化学预防策略。这个特殊应用的目的是确定自分泌il - 8如何促进结肠炎衍生的结肠癌起始细胞（CCICs）的致瘤性。与散发性结直肠癌的CCICs类似，UC的CCICs在体外和体内实验中都是一个很好的模型，可以分析结肠炎向癌症转变的机制。核心假设是，IL8信号是结肠炎向癌症转变所必需的。这项研究的基本原理是，一旦我们了解了il - 8促进肿瘤发生的作用和机制，我们将能够开发出干预从良性结肠炎到恶性癌症进展的方法。跟进我们的强大的初步数据,将被用来测试我们的假设追求三个具体目标:1)定义的影响IL8体内和体外肿瘤的形成来源于主业colitic结肠隔绝,2)来确定下游介质的影响IL8信号的起始肿瘤引起的主业源自colitic冒号,3)划分功能的贡献的p53突变IL8-induced致瘤性的强化。在目的1中，我们将研究外源性il - 8如何影响结肠炎衍生的CCICs的行为，包括增殖、侵袭、肿瘤发生、血管生成和分化。我们将抑制il - 8及其主要受体CXCR1，并确定干扰如何影响这些致瘤性试验。在Aim 2中，我们有证据表明Focal Adhesion Kinase （FAK）是il - 8功能的下游介质。我们将使用RNAi抑制FAK，并在相同的致瘤性实验中描述其变化。目的3涉及R273H p53功能获得突变，我们在每个结肠炎衍生的CCIC分离株中都发现了这种突变。在其他系统中，这种突变与IL8 mRNA的增强和与IL8相关的功能有关。该方法是创新的，因为我们有独特的工具，包括结肠炎的CCICs，并且可以使用散发性结直肠癌的CCICs进行比较。这项提议的研究意义重大，因为它将极大地扩展我们对il - 8如何促进结肠炎相关癌症的理解。

DESCRIPTION (provided by applicant): The pathogenesis of colitis-associated cancer is unclear. Filling this gap in our knowledge is an important challenge because without intervention, up to 18% of patients with chronic ulcerative colitis (UC) will develop colorectal cancer. Thus, our long-term goal is to develop chemopreventive strategies for CAC by defining the mechanisms by which inflammation promotes malignant transformation in patients with chronic ulcerative colitis. The objective of this particular application is to determine how autocrine IL8 contributes to the tumorigenicity of colitis-derived colon cancer initiating cells (CCICs). Similar to CCICs derived from sporadic colorectal cancer, CCICs from UC represent an excellent model for dissecting out mechanisms underlying the colitis-to-cancer transition using both in vitro and in vivo assays. The central hypothesis is that IL8 signaling is required fo the colitis-to-cancer transition. The rationale for the proposed research is that once we understand the contribution and mechanisms by which IL8 promotes tumor initiation, we will be able to develop ways to interfere in the progression from benign colitis to malignant cancer. Following up on our strong preliminary data, our hypothesis will be tested by pursuing three specific aims: 1) to define the effects of IL8 on the in vivo and in vitro formation of tumors derived from CCICs isolated from colitic colon, 2) to determine the influence of downstream mediators of IL8 signaling on the initiation of tumors induced by CCICs derived from colitic colon, and, 3) to delineate the contribution of gain-of-function p53 mutations to IL8-induced potentiation of tumorigenicity. In Aim 1, we will examine how exogenous IL8 influences the behavior of colitis-derived CCICs in assays involving proliferation, invasion, tumorigenesis, angiogenesis and differentiation. We will inhibit both IL8 and its dominant receptor, CXCR1, and determine how interference affects these tumorigenic assays. In Aim 2, we have evidence that Focal Adhesion Kinase (FAK) is a downstream mediator of IL8 function. We will inhibit FAK using RNAi and delineate alterations in the same tumorigenic assays. Aim 3 involves the R273H p53 gain-of-function mutation which we found in each of our colitis-derived CCIC isolates. In other systems, this mutation has been associated with potentiation of IL8 mRNA and functions associated with IL8. The approach is innovative, because we have unique tools including the CCICs from colitis, and can use CCICs from sporadic colorectal cancer for comparison. The proposed research is significant as it will greatly expand our understanding of how IL8 contributes to colitis-associated cancer.