PAI-1-mediated early-onset endometrial cancer

PAI-1介导的早发性子宫内膜癌

基本信息

批准号：
10410371
负责人：
Tim H.-M. Huang
金额：
$ 43.79万
依托单位：
UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-06-01 至 2026-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10410371
关键词：
Address Adhesiveness Adipose tissue Age Atomic Force Microscopy Attenuated Biological Assay Biophysics Blood Caring Cell Polarity Cell Shape Cell surface Cells Clinic Clinical Coculture Techniques DNA Methylation DNA Modification Methylases Development Disadvantaged Disease Dyes Elasticity Endometrial Endometrial Carcinoma Epidemic Epigenetic Process Epithelial Cells Exposure to Expression Profiling Extracellular Matrix Fertility Future Gene Expression Genes Genetic Transcription Growth Health Insurance Homeostasis Hormones Hypermethylation Immune Incidence Infiltration Insulin Resistance Ions Knock-in LDL-Receptor Related Protein 1 Lead Link MADH4 gene Malignant Neoplasms Mediating Medical Metabolic syndrome Methodology Methods Methylation Methyltransferase Modeling Molecular Monitor Obesity Onset of illness Pathway interactions Patients Permeability Phenotype Plasminogen Activator Inhibitor 1 Play Preventive measure Primary Neoplasm Prognosis Property Proteomics Recurrence Repression Risk Role Sample Size Sampling Signal Transduction Signaling Molecule Socioeconomic Factors Stromal Cells Testing Time Tissue Microarray Transforming Growth Factor beta Travel Ubiquitin Up-Regulation adipokines base cancer cell cancer recurrence cancer subtypes cell free DNA cell motility cell type chromatin immunoprecipitation cohort comorbidity demographics early onset epigenetic marker epigenetic silencing experience fertility preservation food desert high body mass index in vivo insight intercellular communication knock-down metaplastic cell transformation methylation biomarker neoplastic novel obese patients paracrine programs promoter protein protein interaction recruit rural area screening single-cell RNA sequencing transcriptional reprogramming tumor tumor microenvironment tumorigenesis

项目摘要

ABSTRACT PAI-1-mediated early-onset endometrial cancer Over the last 15 years, an increase in obesity-associated endometrial cancer has been observed, coinciding with the globesity epidemic in the US. These patients are 15-30 years younger than the typical patient demographics, and thus experience clinical burden linked to fertility preservation and disease recurrence. To understand the contribution of obesity to early-onset endometrial cancer, we recently found increased infiltration of adipose stromal cells (ASCs) in endometrial microenvironments of obese patients. Preliminary studies implicate that ASCs directly influence expression changes of loci associated with intercellular permeability and polarity (IPP) in endometrial epithelial cells (EECs). Single-cell transcriptomic profiling has further identified that plasminogen activator inhibitor-1 (PAI-1), an abundant ASC-secreted adipokine, plays a key role in deregulating IPP functions. Therefore, we hypothesize that aberrant PAI-1 signaling interferes with IPP transcription, disrupting intercellular communication homeostasis to promote neoplastic EECs. In Aim 1, the contribution of ASC-secreted PAI-1 to transcription reprogramming of IPP will be determined in EEC exposure models. When PAI-1 is tethered to LDL receptor-related protein 1 (LRP1) on the cell surface, the internalized signaling engenders E3 ubiquitin-mediated degradation of SMAD4 that attenuates TGFβ tumor- suppressive transcription program. Single-cell proteomic profiling will confirm whether IPP repression preferentially occurs in SMAD4-underexpressed cell subpopulations of primary tumors in young obese patients. In Aim 2, phenotypic influences of PAI-1 on cellular transformation will be assessed in EEC exposure models with IPP knockdowns or knockins. Dye-transfer assay and atomic force microscopy will be used to probe intercellular properties of permeability and polarity in EECs and to determine whether these altered biophysical features represent a neoplastic phenotype of EECs. When validated in a tissue microarray panel of 230 tumors and 30 uninvolved normal samples (sample size justified), decreased expression of candidate loci is expected to correlate with the young age of patients with high body mass indices (BMIs). In Aim 3, PAI-1- mediated recruitment of DNA methyltransferases will be examined in susceptible IPP loci. Persistent exposure of EECs to PAI-1 will facilitate methylation propagation within IPP promoters, leaving permanent epigenetic footprints in the neoplastic progeny. When confirmed in an endometrial cancer cohort, increased DNA methylation of these candidate loci is frequently present in primary tumors of young obese patients. The proposed study not only gives insights into a novel role of PAI-1 in early-onset endometrial cancer, but also identifies epigenetic biomarkers for cell-free DNA monitoring of young patients at risk of developing future recurrence.

抽象的 PAI-1介导的早发性子宫内膜癌在过去 15 年中，观察到与肥胖相关的子宫内膜癌有所增加，同时这些患者比典型患者年轻 15 至 30 岁。人口统计数据，因此经历与生育力保存和疾病复发相关的临床负担。了解肥胖对早发性子宫内膜癌的影响，我们最近发现肥胖增加肥胖患者子宫内膜微环境中脂肪基质细胞（ASC）的浸润。研究表明，ASC 直接影响细胞间相关基因座的表达变化子宫内膜上皮细胞（EEC）的渗透性和极性（IPP）。进一步确定纤溶酶原激活剂抑制剂-1 (PAI-1)，一种丰富的 ASC 分泌的脂肪因子，在因此，我们努力解决异常 PAI-1 信号传导干扰的问题。 IPP 转录，破坏细胞间通讯稳态，促进肿瘤 EEC。 ASC 分泌的 PAI-1 对 IPP 转录重编程的贡献将在 EEC 中确定当 PAI-1 与细胞表面的 LDL 受体相关蛋白 1 (LRP1) 结合时，内化信号传导导致 E3 泛素介导的 SMAD4 降解，从而减弱 TGFβ 肿瘤 - 单细胞蛋白质组分析将确认 IPP 是否受到抑制。优先发生在年轻肥胖者原发肿瘤的 SMAD4 表达不足的细胞亚群中在目标 2 中，将在 EEC 暴露中评估 PAI-1 对细胞转化的表型影响。具有 IPP 敲低或敲入的模型将用于进行染色转移测定和原子力显微镜。探测 EEC 中渗透性和极性的细胞间特性，并确定这些特性是否改变当在组织微阵列中进行验证时，生物物理特征代表了 EEC 的肿瘤表型。 230个肿瘤和30个未受累的正常样本（样本量合理），候选位点表达减少在目标 3 中，PAI-1- 预计与高体重指数 (BMI) 患者的年轻年龄相关。将在易受影响的 IPP 位点中检查介导的 DNA 甲基转移酶的募集。将 EEC 转化为 PAI-1 将促进 IPP 启动子内的甲基化传播，从而留下永久的表观遗传当在子宫内膜癌队列中得到证实时，肿瘤后代中的足迹增加了。这些候选基因座的甲基化经常存在于年轻肥胖患者的原发性肿瘤中。拟议的研究不仅深入了解了 PAI-1 在早发性子宫内膜癌中的新作用，而且确定表观遗传生物标志物，用于监测未来有发育风险的年轻患者的游离 DNA 复发。