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有关，在经济上和患者发病率和死亡率方面都造成了巨大的成本。深入的研究已经集中在识别信号通路，这可能是治疗或化学预防的目标在高危人群。一个候选分子是ErbB-4，它是最近被发现的与egfr相关的酪氨酸激酶生长因子受体ErbB家族的成员。ErbB-4在哺乳动物组织中表达为多达四种不同的全长同种异构体和两种细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在结直肠癌中的表达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)炎症期间肠上皮中ErbB-4表达增加；(2)促炎细胞因子TNF-？促进培养小鼠结肠上皮细胞（MCE）中ErbB-4的表达和激活，以及(3)病理性TNF-？关卡需要ErbB-4。因此，我们提出了一种假设，即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。拟开展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，确定炎症诱导结肠癌对ErbB-4的需求，并确定ErbB-4缺失对AOM/DSS的影响

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.