PAI-1-mediated early-onset endometrial cancer

PAI-1介导的早发性子宫内膜癌

基本信息

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.
摘要 派-1介导的早发性子宫内膜癌 在过去的15年里,肥胖相关的子宫内膜癌的增加已经被观察到, 全球肥胖症在美国的流行。这些患者比典型患者年轻15-30岁 人口统计学上,因此经历与生育力保持和疾病复发相关的临床负担。到 为了了解肥胖对早发性子宫内膜癌的影响,我们最近发现, 肥胖患者子宫内膜微环境中脂肪基质细胞(ASC)浸润。初步 研究表明,ASCs直接影响与细胞间 子宫内膜上皮细胞(EECs)的通透性和极性(IPP)。单细胞转录组学分析 进一步证实,纤溶酶原激活物抑制剂-1(派-1)是一种丰富的ASC分泌的脂肪因子, 在解除对IPP功能的管制方面发挥关键作用。因此,我们假设派-1信号异常干扰了 IPP转录,破坏细胞间通讯稳态以促进肿瘤性内皮细胞。在目标1中, ASC分泌派-1对IPP转录重编程的贡献将在EEC中确定 暴露模型当派-1与细胞表面的LDL受体相关蛋白1(LRP 1)结合时, 内化的信号传导导致E3泛素介导的SMAD 4降解,其减弱TGFβ肿瘤- 抑制转录程序。单细胞蛋白质组分析将证实IPP抑制是否 在年轻肥胖者中,SMAD 4低表达的原发性肿瘤细胞亚群中优先发生。 患者在目标2中,将在EEC暴露中评估派-1对细胞转化的表型影响 具有IPP击倒或敲击的型号。染料转移试验和原子力显微镜将用于 探索内皮细胞的渗透性和极性的细胞间特性,并确定这些特性是否改变 生物物理特征代表了内皮细胞的肿瘤表型。当在组织微阵列面板中验证时, 230例肿瘤和30例未受累正常样本(样本量合理),候选基因座表达降低 预期与具有高体重指数(BMI)的患者的年轻年龄相关。在目标3中,派-1- 将在易感IPP基因座中检查DNA甲基转移酶介导的募集。持续暴露 将促进IPP启动子内的甲基化增殖, 肿瘤后代的足迹当在子宫内膜癌队列中得到证实时, 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。的 这项研究不仅揭示了派-1在早发性子宫内膜癌中的新作用, 确定表观遗传生物标志物,用于对有发展未来风险的年轻患者进行无细胞DNA监测 复发

项目成果

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Tim H.-M. Huang其他文献

ERα-related chromothripsis enhances concordant gene transcription on chromosome 17q11.1-q24.1 in luminal breast cancer
  • DOI:
    10.1186/s12920-020-0729-7
  • 发表时间:
    2020-05-14
  • 期刊:
  • 影响因子:
    2.000
  • 作者:
    Chun-Lin Lin;Xi Tan;Meizhen Chen;Meena Kusi;Chia-Nung Hung;Chih-Wei Chou;Ya-Ting Hsu;Chiou-Miin Wang;Nameer Kirma;Chun-Liang Chen;Ching-Hung Lin;Kate I. Lathrop;Richard Elledge;Virginia G. Kaklamani;Kohzoh Mitsuya;Tim H.-M. Huang
  • 通讯作者:
    Tim H.-M. Huang

Tim H.-M. Huang的其他文献

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{{ truncateString('Tim H.-M. Huang', 18)}}的其他基金

PAI-1-mediated early-onset endometrial cancer
PAI-1介导的早发性子宫内膜癌
  • 批准号:
    10410371
  • 财政年份:
    2021
  • 资助金额:
    $ 43.8万
  • 项目类别:
Interrogating Epigenetic Changes in Cancer Genomes
探究癌症基因组的表观遗传变化
  • 批准号:
    8628066
  • 财政年份:
    2014
  • 资助金额:
    $ 43.8万
  • 项目类别:
Novel epigenetic paradigm in endometrial cancer recurrence
子宫内膜癌复发的新表观遗传学范例
  • 批准号:
    8755016
  • 财政年份:
    2014
  • 资助金额:
    $ 43.8万
  • 项目类别:
Novel epigenetic paradigm in endometrial cancer recurrence
子宫内膜癌复发的新表观遗传学范例
  • 批准号:
    9124596
  • 财政年份:
    2014
  • 资助金额:
    $ 43.8万
  • 项目类别:
Interrogating Epigenetic Changes in Cancer Genomes
探究癌症基因组的表观遗传变化
  • 批准号:
    8340013
  • 财政年份:
    2011
  • 资助金额:
    $ 43.8万
  • 项目类别:
Combinational Environmental Chemicals Altering Susceptibility for Mammary Cancer
组合环境化学物质改变乳腺癌的易感性
  • 批准号:
    8280369
  • 财政年份:
    2010
  • 资助金额:
    $ 43.8万
  • 项目类别:
Combinational Environmental Chemicals Altering Susceptibility for Mammary Cancer
组合环境化学物质改变乳腺癌的易感性
  • 批准号:
    8011571
  • 财政年份:
    2010
  • 资助金额:
    $ 43.8万
  • 项目类别:
Combinational Environmental Chemicals Altering Susceptibility for Mammary Cancer
组合环境化学物质改变乳腺癌的易感性
  • 批准号:
    8472494
  • 财政年份:
    2010
  • 资助金额:
    $ 43.8万
  • 项目类别:
Combinational Environmental Chemicals Altering Susceptibility for Mammary Cancer
组合环境化学物质改变乳腺癌的易感性
  • 批准号:
    8150389
  • 财政年份:
    2010
  • 资助金额:
    $ 43.8万
  • 项目类别:
Epigenomics of Bisphenol A Exposure and Disease Risk
双酚 A 暴露和疾病风险的表观基因组学
  • 批准号:
    7714035
  • 财政年份:
    2009
  • 资助金额:
    $ 43.8万
  • 项目类别:

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  • 批准号:
    04555169
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    1992
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体内衰老红细胞粘附性的研究
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    63570039
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    1988
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    Standard Grant
MOLECULAR BASIS OF CELLULAR ADHESIVENESS
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  • 批准号:
    3163976
  • 财政年份:
    1979
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    1979
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