Role of EFEMP1 in the Pathogenesis of Leiomyoma

EFEMP1 在平滑肌瘤发病机制中的作用

• 批准号: 9351192
• 负责人: Erica E Marsh
• 金额: $ 0.83万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-08-15 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/9351192
• 关键词: Accounting; African American; Age; Anemia; Benign; Biology; Cell Proliferation; Cells; Cellular Morphology; Colorectal Cancer; DNA; DNA Methylation; DNA methyltransferase inhibition; Data; Deoxycytidine; Down-Regulation; Endometrial Carcinoma; Epidermal Growth Factor; Epigenetic Process; Extracellular Matrix; Family; Functional disorder; Gene Expression; Genes; Glycoproteins; Growth; Growth and Development function; Gynecology; Health Care Costs; Human; Hypermethylation; Hysterectomy; Infertility; Instruction; Leiomyoma; Malignant Neoplasms; Malignant neoplasm of lung; Malignant neoplasm of prostate; Modification; Molecular; Morbidity - disease rate; Myometrial; Nature; Normal tissue morphology; One-Step dentin bonding system; Organogenesis; Output; Pathogenesis; Pathway interactions; Pattern; Pelvic Pain; Phenotype; Pilot Projects; Play; Prevalence; Preventive Intervention; Production; Proteins; Public Health; Publishing; Regulation; Research; Role; S1-5 protein; Signal Transduction; Smooth Muscle Myocytes; Symptoms; System; Testing; Therapeutic Intervention; Time; Tissues; Tumor Suppressor Proteins; United States; United States National Institutes of Health; Uterine Fibroids; Uterine Neoplasms; Uterine hemorrhage; Woman; aged; angiogenesis; base; cell growth; differential expression; experimental study; fibulin; knock-down; myometrium; overexpression; programs; reproductive; tumor; tumor growth; tumorigenesis

Leiomyomas are highly pervasive benign tumors of the uterus that have an overall prevalence of 70% in women by the age of 50. They are the leading cause of hysterectomy in the United States, accounting for almost 50% of the 600,000 hysterectomies performed annually and $34 billion dollars in annual healthcare costs. Despite their prevelance and public health impact, the cellular and molecular mechanisms regulating the development and growth of leiomyoma are not well understood. Phenotypically, these tumors are distinct from the adjacent normal tissue largely due to the overproduction of extracellular matrix component. We and others have demonstrated that amongst the differentially expressed genes between LEIO and MYO, is EFEMP1, suggesting a role in the pathogenesis of these tumors. Among the 20 most differentially expressed genes, we identified Epidermal-growth factor-containing fibulin-like extracellular matrix 1 (EFEMP1). EFEMP1 encodes one of the fibulins (fibulin-3; FBLN3), a family of extracellular matrix glycoproteins that has been demonstrated to play roles in angiogenesis, extracellular matrix production, organogenesis, and cell morphology and growth. Differential expression of EFEMP1 has been implicated in tumor growth, angiogenesis, and extracellular matrix production in a number of malignancies. Specifically, the downregulation of EFEMP1 has been demonstrated to promote growth and altered intracellular signaling in prostate, lung, endometrial, and colorectal cancer. Neither the expression pattern nor the role of EFEMP1 and its protein product have been investigated in leiomyomas. Our lab has generated preliminary data that demonstrate that EFEMP1 is markedly downregulated in leiomyomas. Based on its role as a tumor suppressor in various cancers, we hypothesize that aberrant expression of EFEMP1 contributes to the pathophysiology of leiomyomas. We propose to test our hypothesis in two specific aims. In Specific Aim 1 we will determine the contribution of EFEMP1 to the tumorigenesis in leiomyoma. In Specific Aim 2 we will determine the mechanism by which EFEMP1 is differentially expressed in leiomyoma versus myometrium. We predict that the findings generated in this study will bring us one step closer to developing long-term nonhormonal therapeutic and preventative interventions for these highly morbid tumors, underscoring the translational potential of this study.

子宫肌瘤是一种高度弥漫的子宫良性肿瘤，其总体发病率为70%。 女性在50岁之前。它们是美国子宫切除术的主要原因，占 在每年进行的60万例子宫切除手术中，近50%的人每年的医疗保健费用为340亿美元 成本。尽管它们的存在和对公共健康的影响，但调节细胞和分子机制 肌瘤的发展和生长还不是很清楚。在表型上，这些肿瘤是不同的 与邻近的正常组织相比，很大程度上是由于细胞外基质成分的过度产生。我们和 其他人已经证明，在LEIO和MYO之间差异表达的基因中，有 EFEMP1，提示在这些肿瘤的发病机制中起作用。在表达差异最大的20个单词中 基因，我们鉴定了含有表皮生长因子的类纤维蛋白细胞外基质1(EFEMP1)。EFEMP1 编码一种纤维蛋白(纤维蛋白-3；FBLN3)，一种细胞外基质糖蛋白家族，已被 已证实在血管生成、细胞外基质产生、器官形成和细胞中发挥作用 形态和生长。EFEMP1的差异表达与肿瘤生长有关， 一些恶性肿瘤中的血管生成和细胞外基质的产生。具体地说，下调监管 EFEMP1的作用已被证明能促进生长并改变前列腺、肺、 子宫内膜癌和结直肠癌。EFEMP1及其蛋白的表达模式和作用 该产品已在肌瘤中进行了研究。我们的实验室已经生成了初步数据，证明 EFEMP1在肌瘤中的表达明显下调。基于它作为肿瘤抑制因子在各种不同的 我们假设EFEMP1的异常表达参与了肿瘤的病理生理过程。 肌瘤。我们建议在两个具体目标上检验我们的假设。在具体目标1中，我们将确定 EFEMP1在子宫肌瘤发生中的作用在具体目标2中，我们将确定 EFEMP1在子宫肌瘤和子宫肌层中差异表达的机制。我们预测 这项研究产生的发现将使我们更接近于发展长期的非荷尔蒙 对这些高度病态的肿瘤进行治疗性和预防性干预，强调了翻译 这项研究的潜力。