PAI-1-mediated early-onset endometrial cancer

PAI-1介导的早发性子宫内膜癌

• 批准号: 10609901
• 负责人: Tim H.-M. Huang
• 金额: $ 43.8万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
• 依托单位国家: 美国
• 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/10609901
• 关键词: Address; Adhesiveness; Adipose tissue; Age; Atomic Force Microscopy; Attenuated; Biological Assay; Biophysics; Blood; Caring; Cell Polarity; Cell Shape; Cell secretion; Cell surface; Cells; Clinic; Clinical; Coculture Techniques; DNA Methylation; DNA Modification Methylases; DNMT3B gene; Development; Disadvantaged; Disease; Disparity; 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; LDL-Receptor Related Protein 1; 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; Predisposition; Preventive measure; Primary Neoplasm; Prognosis; Proliferating; Property; Protein C Inhibitor; Proteomics; Recurrence; Recurrent Malignant Neoplasm; Recurrent disease; 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; 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

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.

摘要