Multifunctional roles of homeobox gene DLX4 in ovarian cancer

项目摘要/摘要 在被诊断为上皮性卵巢癌(EOC)的女性中，70%患有晚期卵巢癌- 这是一种阶段性疾病，很少能通过手术和常规化疗治愈。理解分子 卵巢癌的发病机制是识别更准确的标志物以提高早期发现的关键，而癌症- 可针对其开发新一代靶向治疗的特定分子改变。我们的目标是 寻找控制卵巢上皮性癌发病机制的新的分子靶点。 许多驱动肿瘤发病的途径是控制正常胚胎的过程的异常 发展。我们发现同源异型盒模式基因DLX4在正常卵巢和卵巢中不表达。 良性囊肿，而在恶性卵巢癌中的表达与腹水、高级别肿瘤密切相关 和疾病晚期。我们对异种移植模型的研究表明，DLX4促进了EOC的生长， 播散、血管化和腹水。我们假设DLX4是一个促进 卵巢上皮性癌的发病机制是通过诱导促血管生成和转移程序来实现的。 这项提议的目标是确定DLX4作为分子开关来诱导 影响卵巢癌发病机制的效应物的表达。我们的具体目标是确定： 1)DLX4控制关键促血管生成、转移因子表达的调控水平 2)DLX4重新编程基因表达的新调控机制 3)这种重新编程机制的临床意义和预后相关性 在其任务和影响方面，这项建议解决了人类生物学基础研究的基本需要。 平等机会委员会。此外，在研究模式基因在肿瘤发病机制中的新调控机制时， 这项研究为癌症如何与胚胎发育密切相关提供了至关重要的见解。

PROJECT SUMMARY/ ABSTRACT Seventy percent of women who are diagnosed with epithelial ovarian cancer (EOC) present with advanced- stage disease and are rarely cured by surgery and conventional chemotherapy. Understanding the molecular pathogenesis of EOC is essential to identify more accurate markers to improve early detection, and cancer- specific molecular alterations against which new-generation targeted therapies can be developed. Our goal is to identify novel molecular focal points that control the multiple pathways that drive the pathogenesis of EOC. Many pathways that drive tumor pathogenesis are aberrations of processes that control normal embryonic development. We have found that the homeobox patterning gene DLX4 is not expressed in normal ovary and benign cysts, whereas its expression in malignant EOC is strongly associated with ascites, high tumor grade and advanced disease stage. Our studies of xenograft models demonstrated that DLX4 promotes EOC growth, dissemination, vascularization and ascites. We hypothesize that DLX4 is a molecular focal point that promotes the pathogenesis of EOC by inducing a pro-angiogenic, metastatic program. The goal of this proposal is to determine the mechanism by which DLX4 acts as a molecular switch to induce expression of effectors that drive EOC pathogenesis. Our specific aims are to determine: 1) the regulatory level at which DLX4 controls expression of key pro-angiogenic, metastatic factors 2) a novel regulatory mechanism by which DLX4 re-programs gene expression 3) the clinical significance and prognostic relevance of this re-programming mechanism In its tasks and implications, this proposal addresses the essential need for basic research of the biology of EOC. Moreover, in investigating novel regulatory mechanisms of a patterning gene in tumor pathogenesis, the study provides critical insight into how cancer is intimately related to embryonic development.