The role of ErbB-4 in inflammation-induced colon carcinogenesis

ErbB-4 在炎症诱导的结肠癌发生中的作用

• 批准号: 7580933
• 负责人: Mark R Frey
• 金额: $ 12.52万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-04-01 至 2012-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7580933
• 关键词: Address; Allografting; Biological Assay; Cell Survival; Cells; Chemoprevention; Chronic; Colitis; Colon; Colon Carcinoma; Colorectal Cancer; Data; Disease; Environment; Epithelial; Epithelial Cells; Epithelium; ErbB4 gene; Family; Family member; Immigration; In Vitro; Individual; Inflammation; Inflammatory; Inflammatory Bowel Diseases; Intestinal Neoplasms; Intestines; Large Intestine Carcinoma; Length; Modeling; Morbidity - disease rate; Mus; Pathologic; Patients; Protein Isoforms; Receptor Protein-Tyrosine Kinases; Relative (related person); Reporting; Research; Risk; Role; Signal Pathway; TNF gene; Testing; Tissues; base; carcinogenesis; cell transformation; colon carcinogenesis; cost; cytokine; early onset; high risk; in vitro Model; in vivo; intestinal epithelium; member; migration; mortality; novel; overexpression; research study; tumor; tumorigenesis

DESCRIPTION (provided by applicant): Inflammatory bowel diseases are associated with increased risk of early-onset colorectal cancer, incurring great cost both economically and in patient morbidity and mortality. Intensive research has been focused on identifying signaling pathways which may be targets of therapy or chemoprevention in high-risk groups. One candidate molecule is ErbB-4, the most recently described member of the EGFR-related ErbB family of tyrosine kinase growth factor receptors. ErbB-4 is expressed in mammalian tissues as up to four distinct full length isoforms and two intercellular domain cleavage products, and is likely to participate in regulatory mechanisms distinct from those of other ErbB family members. Recent reports have shown ErbB-4 expression in colorectal carcinomas and a possible association with more aggressive disease, though the mechanisms underlying these data are unknown. Our preliminary results indicate that (1) ErbB-4 expression is increased in the intestinal epithelium during inflammation, (2) the proinflammatory cytokine TNF-? promotes ErbB-4 expression and activation in cultured mouse colon epithelial (MCE) cells, and (3) cell survival in the presence of pathologic TNF-? levels requires ErbB-4. Therefore we have developed the hypothesis that ErbB-4 isoforms promote chronic inflammation-induced colon carcinogenesis through increased cell survival, proliferation, and/or migration in the inflammatory environment. Proposed experiments will address this hypothesis through the following specific Aims: (1) Determine the requirement for ErbB-4 in inflammation-induced colon cancer by characterizing expression of ErbB-4 isoforms during tumorigenesis and determining the effect of ErbB-4 deletion on AOM/DSS tumorigenesis in vivo; (2) Define the role(s) of full-length and intracellular domain ErbB-4 isoforms in intestinal cell transformation by expressing individual ErbB-4 forms in ErbB-4-/- MCE cells and using these cells for in vitro transformation assays; and (3) Test the effect of ErbB-4 isoforms on intestinal tumor formation in vivo using an allograft tumor formation model. Overall, these studies are expected to clarify the role of ErbB-4 in colitis-associated carcinogenesis. They will also provide much-needed information on the relative roles of the different ErbB-4 isoforms in tissues that express multiple forms, and will potentially identify novel avenues of therapy and chemoprevention based on the activity these isoforms.

描述(由申请人提供)：炎症性肠病与早发性结直肠癌风险增加有关，在经济和患者发病率和死亡率方面都会招致巨大的成本。密集的研究集中在确定信号通路，这些信号通路可能是高危人群治疗或化学预防的目标。一个候选分子是ErbB-4，它是最近被描述的与EGFR相关的酪氨酸激酶生长因子受体ErbB家族的成员。ErbB-4在哺乳动物组织中以四种不同的全长异构体和两种胞间结构域裂解产物的形式表达，可能参与不同于ErbB家族其他成员的调控机制。最近的报告显示ErbB-4在结直肠癌中的表达，并可能与更具侵袭性的疾病有关，尽管这些数据背后的机制尚不清楚。我们的初步结果表明：(1)在炎症过程中，ErbB-4在肠上皮细胞中的表达增加；(2)促炎细胞因子TNF-？促进ErbB-4在培养的小鼠结肠上皮(MCE)细胞中的表达和激活，以及(3)细胞在病理性肿瘤坏死因子？级别需要ErbB-4。因此，我们提出了一个假设，即ErbB-4亚型通过增加炎症环境中细胞的存活、增殖和/或迁移，促进慢性炎症诱导的结肠癌的发生。拟议的实验将通过以下具体目标来解决这一假说：(1)通过表征ErbB-4亚型在肿瘤发生过程中的表达并确定ErbB-4缺失对AOM/DSS的影响，确定炎症诱导的结肠癌对ErbB-4的需求 通过在ErbB-4-/-MCE细胞中表达单个ErbB-4亚型并将其用于体外转化试验，确定了全长及胞内结构域ErbB-4亚型在肠细胞转化中的作用(S)；以及(3)通过同种异体肿瘤形成模型检测ErbB-4亚型在体内肠道肿瘤形成中的作用。总体而言，这些研究有望阐明ErbB-4在结肠炎相关癌症发生中的作用。他们还将提供急需的信息，关于不同的ErbB-4亚型在表达多种形式的组织中的相对作用，并可能根据这些亚型的活性确定治疗和化学预防的新途径。