Multifunctional roles of homeobox gene DLX4 in ovarian cancer

同源盒基因DLX4在卵巢癌中的多功能作用

• 批准号: 7887364
• 负责人: Honami Naora
• 金额: $ 32.79万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-04-01 至 2015-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7887364
• 关键词: 5' Untranslated Regions; Address; Aggressive behavior; Angiogenic Factor; Ascites; Basic Science; Benign Ovarian Cyst; Biology; Cessation of life; Chromosome Mapping; Conventional Surgery; Diagnosis; Disease; Elements; Embryo; Embryonic Development; Epithelial ovarian cancer; FGF2 gene; Female; Fibroblast Growth Factor 2; Gene Expression; Generations; Genes; Genetic Translation; Goals; Growth; Homeobox; Homeobox Genes; Malignant - descriptor; Malignant Neoplasms; Malignant neoplasm of ovary; Mediating; Molecular; Morbidity - disease rate; Pathogenesis; Pathway interactions; Pattern; Process; Role; Screening for cancer; Site; Staging; Therapeutic Intervention; Vascular Endothelial Growth Factors; Vascularization; Woman; Xenograft Model; advanced disease; angiogenesis; chemotherapy; clinically significant; improved; insight; intraperitoneal; mortality; neoplastic cell; novel; outcome forecast; overexpression; prognostic; programs; public health relevance; stem; transcription factor; tumor; tumor growth

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.

描述（由申请人提供）：70% 被诊断患有上皮性卵巢癌 (EOC) 的女性已处于晚期疾病，并且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识别更准确的标记物以改善早期检测和癌症特异性分子改变至关重要，从而开发新一代靶向治疗。我们的目标是确定控制 EOC 发病机制的多种途径的新分子焦点。许多驱动肿瘤发病机制的途径是控制正常胚胎发育过程的畸变。我们发现同源盒模式基因DLX4在正常卵巢和良性囊肿中不表达，而其在恶性EOC中的表达与腹水、高肿瘤级别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、传播、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、转移程序来促进 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 发病机制的效应子表达的机制。我们的具体目标是确定：1​​) DLX4 控制关键促血管生成、转移因子表达的调节水平 2) DLX4 重新编程基因表达的新调节机制 3) 这一研究的临床意义和预后相关性-编程机制 在其任务和含义中，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基因的新调控机制时，该研究提供了关于癌症如何与胚胎发育密切相关的重要见解。 公共健康相关性：该提案针对上皮性卵巢癌的研究，这是一种人们知之甚少的疾病，其特点是侵袭性传播，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。