The role of IL8 in colitis-associated tumor initiation

IL8 在结肠炎相关肿瘤发生中的作用

• 批准号: 8624541
• 负责人: Emina HUI-NA Huang
• 金额: $ 31.9万
• 依托单位: CLEVELAND CLINIC LERNER COM-CWRU
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-11-01 至 2017-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8624541
• 关键词: Affect; Benign; Binding; Biological Assay; Cancer Etiology; Cell Proliferation; Cells; Chemopreventive Agent; Chemosensitization; Chronic; Colitis; Colon; Colon Carcinoma; Colonoscopy; Colorectal Cancer; Data; Development; Diagnosis; Dysplasia; Early Diagnosis; Epithelium; Face; Focal Adhesion Kinase 1; Goals; Human; IL8 gene; IL8RA gene; In Vitro; Inflammation; Interleukin 8A Receptor; Intervention; Investigation; Knowledge; Large Intestine Carcinoma; Link; Malignant - descriptor; Malignant Neoplasms; Mediating; Mediator of activation protein; Messenger RNA; Mission; Modeling; Mutation; Neoplasm Metastasis; Non-Malignant; Pathogenesis; Patients; Prevention therapy; Proliferating; Proteomics; Public Health; RNA Interference; Reporting; Research; Risk; Role; Signal Transduction; Specimen; System; Testing; Tumor-Derived; Tumorigenicity; Ulcerative Colitis; Up-Regulation; Work; Xenograft procedure; angiogenesis; autocrine; behavior influence; chemokine; colitis associated cancer; colon cancer cell line; disability; gain of function; gain of function mutation; in vivo; innovation; insight; migration; novel; promoter; receptor; response; self-renewal; therapeutic target; tool; tumor; tumor initiation; tumorigenesis; tumorigenic

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.

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个重要的挑战，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变的机制来制定CAC的化学预防策略。该特定应用的目的是确定自分泌IL 8如何有助于结肠炎衍生的结肠癌起始细胞（CCIC）的致瘤性。与源自散发性结直肠癌的CCIC类似，来自UC的CCIC代表了使用体外和体内测定来剖析结肠炎向癌症转变的潜在机制的极好模型。核心假设是IL 8信号传导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良性结肠炎向恶性癌症发展的方法。根据我们强有力的初步数据，我们的假设将通过追求三个具体目标进行测试：1）确定IL 8对源自从结肠炎结肠分离的CCIC的肿瘤的体内和体外形成的作用，2）确定IL 8信号传导的下游介质对源自结肠炎结肠的CCIC诱导的肿瘤的起始的影响，以及，3）描述功能获得性p53突变对IL 8诱导的致瘤性增强的贡献。在目标1中，我们将研究外源性IL 8如何影响结肠炎衍生的CCIC在涉及增殖、侵袭、肿瘤发生、血管生成和分化的测定中的行为。我们将抑制IL 8及其主要受体CXCR 1，并确定干扰如何影响这些致瘤性测定。在目的2中，我们有证据表明，粘着斑激酶（FAK）是IL 8功能的下游介质。我们将使用RNAi抑制FAK，并在相同的致瘤试验中描绘改变。目的3涉及R273H p53功能获得性突变，我们在每一个结肠炎来源的CCIC分离株中发现了该突变。在其他系统中，该突变与IL 8 mRNA的增强和与IL 8相关的功能相关。这种方法是创新的，因为我们有独特的工具，包括结肠炎的CCIC，并且可以使用散发性结直肠癌的CCIC进行比较。这项研究意义重大，因为它将大大扩展我们对IL 8如何促进结肠炎相关癌症的理解。