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: 7389578
• 负责人: Mark R Frey
• 金额: $ 12.23万
• 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/7389578
• 关键词: Address; Allografting; Biological Assay; Cell Survival; Cells; Chemoprevention; Chronic; Colitis; Colon; Colon Carcinoma; Colorectal Cancer; Condition; Data; Disease; Environment; Epithelial; Epithelial Cells; Epithelium; ErbB4 gene; Family; Family member; Genus Cola; 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; Protein Overexpression; 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; in vitro Model; in vivo; intestinal epithelium; member; migration; mortality; novel; 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）：炎症性肠道疾病与早期结直肠癌的风险增加有关，在经济上以及患者的发病率和死亡率上都产生了巨大的成本。密集研究一直集中在识别可能是高危组中治疗或化学预防靶标的信号通路上。一个候选分子是ERBB-4，它是与EGFR相关的ERBB家族的酪氨酸激酶生长因子受体的最新成员。 ERBB-4在哺乳动物组织中表示为多达四种不同的全长同工型和两个细胞间域的裂解产物，并且很可能参与与其他ERBB家族成员不同的调节机制。最近的报道表明，尽管这些数据尚不清楚，但大肠癌中的ERBB-4表达和可能与更具侵略性疾病的可能关联。我们的初步结果表明，（1）炎症期间肠上皮的ERBB-4表达增加，（2）促炎性细胞因子TNF-？促进培养的小鼠结肠上皮（MCE）细胞中的ERBB-4表达和激活，以及（3）在存在病理TNF-的情况下细胞存活。水平需要ERBB-4。因此，我们已经开发了以下假设：ERBB-4同工型通过在炎症环境中增加的细胞存活，增殖和/或迁移来促进慢性炎症引起的结肠癌发生。提出的实验将通过以下特定目的解决这一假设：（1）通过表征肿瘤发生过程中ERBB-4同工型的表达并确定ERBB-4缺失对AOM/DSS对AOM/DSS的影响，确定ERBB-4在炎症引起的结肠癌中的需求。 体内肿瘤发生； （2）通过在ERBB-4 - / - MCE细胞中表达单个ERBB-4形式，并使用这些细胞进行体外转化测定法，来定义肠细胞转化中全长和细胞内ERBB-4同工型的作用； （3）使用同种异体移植肿瘤形成模型测试ERBB-4同工型对体内肠道肿瘤形成的影响。总体而言，这些研究有望阐明ERBB-4在与结肠炎相关的癌变中的作用。他们还将提供有关表达多种形式的组织中不同ERBB-4同工型相对作用的急需的信息，并根据这些同工型的活性有可能识别治疗和化学预防的新型途径。