Regulation of cyclooxygenase-2 by ErbB4 in colon epithelial cells

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，导致经济上的巨大成本以及患者发病率和死亡率。深入的研究一直集中在识别炎症和癌症中的信号通路，因此可能成为治疗或化学预防的目标。ErbB 4酪氨酸激酶是表皮生长因子相关ErbB生长因子受体家族的一员，在结肠炎和一部分人结直肠癌中表达水平升高。因此，该受体是结肠炎相关肿瘤发生的候选参与者。我们最近证明，ErbB 4的表达和活性是由肿瘤坏死因子诱导的，并且ErbB 4反过来在促炎细胞因子存在下促进结肠上皮细胞的存活。为该应用开发的初步数据进一步显示，ErbB 4在体外和体内模型中都促进结肠上皮细胞转化。此外，ErbB 4诱导的细胞存活和转化与前列腺素合酶环氧合酶-2（考克斯-2）的mRNA稳定性和蛋白水平增加相关。因此，本申请提出检验ErbB 4通过考克斯-2依赖性机制促进炎症环境中结肠上皮细胞存活和转化的假设。计划的实验将使用协调的体外（信号转导分析、细胞凋亡和集落形成测定）和体内（裸鼠异种移植肿瘤形成测定）方法来（1）鉴定参与ErbB 4诱导的考克斯-2表达的信号通路，和（2）研究ErbB 4和考克斯-2在结肠上皮细胞存活和转化中的协作。

DESCRIPTION (provided by applicant): Inflammatory bowel diseases are associated with an increased risk of early-onset colorectal cancer, resulting in great cost both economically and in patient morbidity and mortality. Intensive research has been focused on identifying signaling pathways active in both inflammation and cancer, which may thus be targets of therapy or chemoprevention. The ErbB4 tyrosine kinase, a member of the epidermal growth factor-related ErbB growth factor receptor family, is expressed at elevated levels in colitis and in a subset of human colorectal cancers. This receptor is thus a candidate participant in colitis-associated tumorigenesis. We recently demonstrated that ErbB4 expression and activity are induced by tumor necrosis factor, and that ErbB4 in turn promotes colon epithelial cell survival in the presence of pro-inflammatory cytokines. Preliminary data developed for this application further show that ErbB4 promotes colon epithelial cell transformation in both in vitro and in vivo models. Furthermore, ErbB4-induced cell survival and transformation are associated with increased mRNA stability and protein levels for the prostaglandin synthase cyclooxygenase-2 (COX-2). Thus, this application proposes to test the hypothesis that ErbB4 promotes colon epithelial cell survival and transformation in the inflammatory milieu through a COX-2-dependent mechanism. Planned experiments will use coordinated in vitro (signal transduction analysis, apoptosis & and colony formation assays) and in vivo (nude mouse xenograft tumor formation assays) approaches to (1) Identify signaling pathways involved in ErbB4-induced COX-2 expression, and (2) investigate cooperation between ErbB4 and COX-2 in colon epithelial cell survival and transformation.