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

描述（由申请人提供）：炎症性肠病与早发性结直肠癌的风险增加相关，在经济上以及患者发病率和死亡率方面都产生了巨大的成本。密集的研究一直集中在确定可能成为高危人群治疗或化学预防靶点的信号通路。一个候选分子是ErbB-4，最近描述的EGFR相关的酪氨酸激酶生长因子受体ErbB家族的成员。ErbB-4在哺乳动物组织中表达为多达四种不同的全长同种型和两种胞间结构域切割产物，并且可能参与不同于其他ErbB家族成员的调节机制。最近的报道显示ErbB-4在结直肠癌中表达，并且可能与更具侵袭性的疾病相关，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）ErbB-4表达增加，在肠上皮细胞在炎症，（2）促炎细胞因子TNF-？促进ErbB-4的表达和激活培养的小鼠结肠上皮（MCE）细胞，和（3）在病理性TNF-？水平需要ErbB-4。因此，我们提出了ErbB-4亚型通过增加炎症环境中的细胞存活、增殖和/或迁移来促进慢性炎症诱导的结肠癌发生的假设。提出的实验将通过以下具体目的来解决这一假设：（1）通过表征肿瘤发生过程中ErbB-4亚型的表达并确定ErbB-4缺失对AOM/DSS的影响来确定炎症诱导的结肠癌中对ErbB-4的需要 体内肿瘤发生;（2）通过在ErbB-4-/- MCE细胞中表达单独的ErbB-4形式并使用这些细胞进行体外转化测定来确定全长和细胞内结构域ErbB-4同种型在肠细胞转化中的作用;和（3）使用同种异体移植物肿瘤形成模型测试ErbB-4同种型对体内肠肿瘤形成的作用。总的来说，这些研究有望阐明ErbB-4在结肠炎相关致癌作用中的作用。它们还将提供关于不同ErbB-4亚型在表达多种形式的组织中的相对作用的急需信息，并将潜在地基于这些亚型的活性确定治疗和化学预防的新途径。

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.