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.

平滑肌瘤是一种高度普遍的子宫良性肿瘤，在女性中的总体患病率为 70% 50 岁以下的女性。她们是美国子宫切除术的主要原因，占 每年进行的 600,000 例子宫切除术中的近 50% 以及每年 340 亿美元的医疗保健费用 成本。尽管它们很常见并影响公共健康，但调节它们的细胞和分子机制 平滑肌瘤的发展和生长尚不清楚。在表型上，这些肿瘤是不同的 来自邻近正常组织的大部分是由于细胞外基质成分的过量产生。我们和 其他人已经证明，在 LEIO 和 MYO 之间差异表达的基因中， EFEMP1，表明在这些肿瘤的发病机制中发挥作用。在表达差异最大的 20 个中 基因，我们鉴定出含有表皮生长因子的纤维蛋白样细胞外基质 1 (EFEMP1)。 EFMP1 编码 fibulin 之一（fibulin-3；FBLN3），这是一种细胞外基质糖蛋白家族，已被 被证明在血管生成、细胞外基质产生、器官发生和细胞 形态和生长。 EFEMP1 的差异表达与肿瘤生长有关， 许多恶性肿瘤中的血管生成和细胞外基质产生。具体来说，下调 EFEMP1 已被证明可以促进前列腺、肺、 子宫内膜癌和结直肠癌。 EFEMP1及其蛋白的表达模式和作用均不存在 产品已在平滑肌瘤中进行了研究。我们的实验室已生成初步数据表明 EFEMP1 在平滑肌瘤中显着下调。基于其在多种肿瘤抑制中的作用 在癌症中，我们假设 EFEMP1 的异常表达有助于癌症的病理生理学 平滑肌瘤。我们建议在两个特定目标中检验我们的假设。在具体目标 1 中，我们将确定 EFEMP1 对平滑肌瘤肿瘤发生的贡献。在具体目标 2 中，我们将确定 EFEMP1 在平滑肌瘤和子宫肌层中差异表达的机制。我们预测 这项研究的结果将使我们离开发长期非激素疗法更近了一步。 针对这些高发病率肿瘤的治疗和预防干预措施，强调了转化 这项研究的潜力。