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: 8445300
• 负责人: Honami Naora
• 金额: $ 29.89万
• 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/8445300
• 关键词: 17q21.3; 5' Untranslated Regions; Address; Aggressive behavior; Angiogenic Factor; Ascites; Basic Science; Benign Ovarian Cyst; Beryllium; Biology; Cessation of life; Chromosome Mapping; Conventional Surgery; Diagnosis; Disease; 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; Messenger RNA; 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; stem; transcription factor; tumor; tumor growth

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.

项目摘要/摘要 被诊断为上皮卵巢癌（EOC）的女性中有百分之七十 阶段疾病，很少通过手术和常规化学疗法治愈。了解分子 EOC的发病机理对于确定更准确的标记以改善早期检测和癌症至关重要。 可以开发针对新一代靶向疗法的特定分子改变。我们的目标是 确定控制驱动EOC发病机理的多种途径的新型分子焦点。 许多驱动肿瘤发病机理的途径是控制正常胚胎的过程的畸变 发展。我们发现，同源型构图基因DLX4在正常卵巢中未表达，并且 良性囊肿，而其在恶性EOC中的表达与腹水强烈相关，高肿瘤等级 和晚期疾病阶段。我们对异种移植模型的研究表明，DLX4促进EOC的增长， 传播，血管化和腹水。我们假设DLX4是促进的分子焦点 EOC通过诱导促血管生成的转移性程序的发病机理。 该建议的目的是确定DLX4充当分子转换的机制 驱动EOC发病机理的效应子的表达。我们的具体目的是确定： 1）DLX4控制关键前血管生成，转移性因子的表达的调节水平 2）DLX4重新编程基因表达的新型调节机制 3）这种重新编程机制的临床意义和预后相关性 在其任务和含义中，该提案解决了对生物学基础研究的基本需求 EOC。此外，在研究肿瘤发病机理中图案基因的新调节机制时， 研究提供了有关癌症与胚胎发育密切相关的关键见解。