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造成巨大成本。深入研究的重点是确定可能成为高危人群治疗或化学预防目标的信号通路。 ErbB-4 是一种候选分子，它是酪氨酸激酶生长因子受体 EGFR 相关 ErbB 家族中最新描述的成员。 ErbB-4 在哺乳动物组织中表达为多达四种不同的全长亚型和两种细胞间结构域裂解产物，并且可能参与与其他 ErbB 家族成员不同的调节机制。最近的报告显示 ErbB-4 在结直肠癌中表达，并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）炎症期间肠上皮中的 ErbB-4 表达增加，（2）促炎细胞因子 TNF-α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) 在存在病理性 TNF-α 的情况下细胞存活水平需要 ErbB-4。因此，我们提出了这样的假设：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。拟议的实验将通过以下具体目标来解决这一假设：（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，确定炎症诱导的结肠癌对 ErbB-4 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，确定全长和胞内结构域 ErbB-4 同工型在肠细胞转化中的作用； (3)使用同种异体移植肿瘤形成模型测试ErbB-4亚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 在结肠炎相关癌发生中的作用。他们还将提供急需的有关不同 ErbB-4 同工型在表达多种形式的组织中的相对作用的信息，并有可能根据这些同工型的活性确定新的治疗和化学预防途径。

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.