Hypovitaminosis D promotes MED12-associated genomic instability in uterine fibroids

维生素 D 缺乏促进子宫肌瘤中 MED12 相关基因组不稳定性

• 批准号: 10330261
• 负责人: Ayman Al-Hendy
• 金额: $ 8.82万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-02-15 至 2023-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10330261
• 关键词: Accounting; Address; Affect; Africa; Africa South of the Sahara; African; African American; Animal Model; Apoptosis; BRCA1 gene; Benign; Biochemical; Caucasians; Cell Proliferation; Cell model; Chicago; Cholecalciferol; Chromosomal Loss; Chromosomal Rearrangement; Collaborations; Complement; Consent; DNA Damage; DNA Double Strand Break; DNA Repair Pathway; Development; Down-Regulation; Epigallocatechin Gallate; Ethnic Origin; Etiology; Experimental Designs; Female Genital Neoplasms; Fertility; Fibroid Tumor; Fibrous capsule of kidney; Freezing; Funding; Future; Gene Expression; Gene Expression Profiling; Genes; Genetic; Genetic Transcription; Genomic Instability; Ghana; Goals; Health; Health Care Costs; Hospitals; Human; Hysterectomy; Impairment; In Vitro; Incidence; Inflammation; Infrastructure; Intervention; Kenya; Leiomyoma; Lesion; Link; Mediator of activation protein; Medical; Medical center; Modeling; Molecular; Morbidity - disease rate; National Institute of Child Health and Human Development; Natural Products; Operative Surgical Procedures; Oral; Pathogenesis; Pathway interactions; Patients; Perioperative; Premenopause; Procedures; Process; Protocols documentation; Publishing; Race; Receptor Signaling; Relative Risks; Reporting; Research; Research Priority; Risk; Sampling; Savings; Serum; Ships; Signal Pathway; Signal Transduction; Somatic Mutation; Supplementation; Therapeutic; Therapeutic Embolization; Therapeutic Intervention; Time; Tissues; Training; Treatment Efficacy; Tumor Burden; Universities; Uterine Fibroids; Uterine myomectomy; Vitamin D; Vitamin D Deficiency; Vitamin D3 Receptor; Vitamin Deficiency; Woman; Women' s Health; base; black women; cost effective; cost estimate; design; driving force; fertility preservation; gene repair; health disparity; healthy pregnancy; human model; innovation; mortality; mouse model; mutant; myometrium; neoplastic; novel; parent grant; pre-clinical; racial disparity; response; stem cells; transcriptome sequencing; transcriptomics; tumor; tumor growth; tumor progression

Abstract of Funded Parent Grant UFs (leiomyomas) are the most important benign neoplastic threat to women’s health worldwide, with annual health care costs estimated in the hundreds of billions of dollars. UF caused- morbidities negatively impact women of all ethnicities, but disproportionately affect African American (AA) women, who have a threefold higher incidence rate and relative risk of UFs than Caucasian (CC) women. While the basis for this risk disparity is not fully understood, recent studies implicate hypovitaminosis D as a major contributor. Thus, AA women have a tenfold increased risk of vitamin D deficiency compared to CC women, and as we first reported, UF risk is inversely correlated with 25-hydroxy vitamin D serum levels. Nonetheless, it is not clear whether and how the processes that drive UF formation and racial risk disparity are genetically or biochemically linked. Herein, we suggest a mechanistic basis to couple UF etiology and relative risk association through a functional interplay between vitamin D3 and an altered DNA damage response network in MED12-mutant UFs, and further offer proof of concept for therapeutic intervention in this genetic setting. Recently, we and others identified somatic mutations in the transcriptional Mediator subunit MED12 as the dominant drivers of UFs, accounting for ~70% of tumors. Notably, MED12-mutant UFs are characterized by significant chromosomal loss and rearrangement, suggesting genomic instability as a driving force in tumor progression. Herein, we clarify the molecular basis for mutant MED12-driven genomic instability, and further identify vitamin D3 receptor signaling as a likely suppressor of this process. We show that MED12-mutant UF stem cells (SCs) accumulate high levels of unrepaired DNA double-strand breaks (DSBs) through downregulation of key DNA damage response (DDR) and repair genes, including RAD50, RAD51 and BRCA1. Notably, we find the vitamin D3/receptor axis to be a variable modulator of MED12-regulated DDR gene expression. Thus, we show that reduced vitamin D3/receptor signaling suppresses, while elevated signaling activates, DDR genes downregulated in MED12-mutant UF SCs. Based on these findings, we hypothesize that hypovitaminosis D exacerbates DNA damage accumulation and genomic instability arising in MED12-mutant UFs, leading to enhanced tumor progression and burden. Accordingly, we propose that vitamin D3, through reparation of an impaired DDR, will provide therapeutic benefit in MED12-mutant tumors. To confirm and extend these hypotheses, we propose the following aims, which directly address and mechanistically connect three overarching issues in the field: the molecular pathogenesis of UFs, the racial disparity in UF risk, and the development of novel tolerable fertility-saving and cost-effective oral therapies for UFs.

资助父母补助金摘要 UFs（平滑肌瘤）是全球女性健康最重要的良性肿瘤威胁， 每年的医疗费用估计达数千亿美元。UF引起的- 发病率对所有族裔的妇女都有负面影响，但对非洲妇女的影响更大。 美国（AA）妇女，谁有三倍高的发病率和相对风险的UF比 高加索（CC）女性。虽然这种风险差异的基础尚未完全理解，但最近 研究表明维生素D缺乏症是主要原因。因此，AA女性有十倍的 与CC女性相比，维生素D缺乏的风险增加，正如我们首次报道的那样，UF风险 与25-羟基维生素D血清水平呈负相关。然而，尚不清楚是否 以及驱动UF形成和种族风险差异的过程是如何遗传或 生物化学联系。在此，我们提出了一个机制的基础，夫妇UF病因和相关的 通过维生素D3和改变的DNA损伤之间的功能性相互作用的风险关联 MED12突变型UF中的反应网络，并进一步为治疗性UFs提供概念证明。 在这种遗传背景下的干预。最近，我们和其他人发现了体细胞突变， 转录介导子亚基MED12是UF的主要驱动因子，约占UF的70%。 肿瘤的值得注意的是，MED12突变型UF的特征在于显著的染色体丢失， 这表明基因组不稳定性是肿瘤进展的驱动力。在此我们 阐明突变MED12驱动的基因组不稳定性的分子基础，并进一步确定 维生素D3受体信号传导作为这一过程的可能抑制剂。我们发现MED12突变体 UF干细胞（SC）积累高水平的未修复的DNA双链断裂（DSB） 通过下调关键的DNA损伤反应（DDR）和修复基因，包括RAD 50， RAD51和BRCA1。值得注意的是，我们发现维生素D3/受体轴是一个可变的调节剂， MED12调节DDR基因表达。因此，我们表明，减少维生素D3/受体， 信号抑制，而信号升高 激活，DDR基因在MED12突变UF SC中下调。基于这些发现，我们 假设维生素D缺乏症加剧了DNA损伤积累和基因组 MED12突变型UF中出现的不稳定性，导致肿瘤进展和负荷增强。 因此，我们建议，维生素D3，通过修复受损的DDR，将提供 MED12突变型肿瘤的治疗益处。为了证实和扩展这些假设，我们 我提出以下目标，直接解决和机械连接三个 该领域的首要问题：UF的分子发病机制，UF的种族差异 风险，并开发新的可耐受的生育率节省和成本效益的口服疗法， UFs。