Multifunctional roles of homeobox gene DLX4 in ovarian cancer

描述（由申请人提供）：70%被诊断为上皮性卵巢癌（EOC）的妇女表现为晚期疾病，很少通过手术和常规化疗治愈。了解EOC的分子发病机制对于鉴定更准确的标志物以改善早期检测和癌症特异性分子改变至关重要，针对这些改变可以开发新一代靶向治疗。我们的目标是确定新的分子焦点，控制多种途径，驱动EOC的发病机制。许多驱动肿瘤发病的途径是控制正常胚胎发育的过程的畸变。我们已经发现同源异型盒基因DLX4在正常卵巢和良性囊肿中不表达，而其在恶性卵巢上皮性癌中的表达与腹水、高肿瘤分级和晚期疾病阶段密切相关。我们对异种移植模型的研究表明，DLX4促进EOC生长、扩散、血管化和腹水。我们假设DLX4是一个分子焦点，通过诱导促血管生成的转移程序促进EOC的发病机制。该提案的目标是确定DLX4作为分子开关诱导驱动EOC发病机制的效应物表达的机制。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）该重新编程机制的临床意义和预后相关性。在其任务和意义中，该提案解决了EOC生物学基础研究的基本需求。此外，在研究肿瘤发病机制中模式化基因的新调控机制时，该研究为癌症如何与胚胎发育密切相关提供了重要见解。 公共卫生相关性：这项建议是针对上皮性卵巢癌的研究，这是一种知之甚少的疾病，其特征是侵袭性传播，是女性癌症死亡的第五大原因。我们将研究上皮性卵巢癌中胚胎模式基因失调促进肿瘤生长、扩散、血管生成和腹水的新机制。

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE: This proposal is directed to the study of epithelial ovarian cancer, a poorly-understood disease that is characterized by aggressive dissemination and is the fifth leading cause of female cancer death. We will study novel mechanisms by which deregulation of an embryonic patterning gene in epithelial ovarian cancer promotes tumor growth, dissemination, angiogenesis and ascites.