Role of EFEMP1 in the Pathogenesis of Leiomyoma

平滑肌瘤是一种高度弥漫性的子宫良性肿瘤， 50岁的女性。它们是美国子宫切除术的主要原因，占 在每年进行的60万例直肠切除术中， 成本尽管它们的流行和对公共卫生的影响，但调节它们的细胞和分子机制 平滑肌瘤的发展和生长还不清楚。表型上，这些肿瘤是不同的 从邻近的正常组织中分离出来，这主要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之间的差异表达基因中， EFEMP 1，表明在这些肿瘤的发病机制中的作用。在20个差异表达最大的基因中， 基因，我们确定了表皮生长因子含有纤维蛋白样细胞外基质1（EFEMP 1）。EFEMP1 编码一种纤蛋白（fibulin-3; FBLN 3），这是一个细胞外基质糖蛋白家族， 证实在血管生成、细胞外基质产生、器官形成和细胞增殖中发挥作用。 形态和生长。EFEMP 1的差异表达与肿瘤生长有关， 血管生成和细胞外基质的产生。具体来说，下调 已经证明EFEMP 1的表达促进前列腺，肺， 子宫内膜癌和结肠直肠癌。EFEMP 1及其蛋白的表达模式和作用均不清楚。 产品已在平滑肌瘤中进行了研究。我们的实验室已经生成了初步数据， EFEMP 1在平滑肌瘤中显著下调。基于其作为肿瘤抑制剂在各种 我们假设EFEMP 1的异常表达有助于肿瘤的病理生理学， 平滑肌瘤我们建议在两个特定的目标来测试我们的假设。在具体目标1中，我们将确定 EFEMP 1在平滑肌瘤发生中的作用。在具体目标2中，我们将确定 EFEMP 1在平滑肌瘤和子宫肌层中差异表达的机制。我们预测 这项研究的发现将使我们更接近于开发长期非激素性的 治疗和预防性干预这些高度病态的肿瘤，强调翻译 这项研究的潜力。

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.