Exploring the role of progestin and vitamin D on inflammation and oxidative stress in in vitro and in vivo models of ovarian cancer

探索孕激素和维生素 D 对卵巢癌体外和体内模型炎症和氧化应激的作用

• 批准号: 10064375
• 负责人: Gustavo Rodriguez
• 金额: $ 6.51万
• 依托单位: NORTHSHORE UNIVERSITY HEALTHSYSTEM
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-12-01 至 2022-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10064375
• 关键词: Abdominal Cavity; Affect; Benign; Biological; Biological Assay; C-reactive protein; CD3 Antigens; CD44 gene; Calcitriol; Carcinoma in Situ; Cell Line; Cell Nucleus; Cells; DNA; DNA Damage; Development; Disease model; Dominant-Negative Mutation; Enzyme-Linked Immunosorbent Assay; Epithelial; Epithelium; Event; Exposure to; Female; Formulation; Genes; Gynecologic Surgical Procedures; H2AFX gene; Hydrogen Peroxide; IL8 gene; ITGAM gene; Immunofluorescence Immunologic; Immunohistochemistry; In Vitro; Incidence; Inflammation; Inflammation Mediators; Inflammatory; Interleukin-6; Knockout Mice; Lead; Lesion; Levonorgestrel; MS4A1 gene; Malignant Neoplasms; Malignant neoplasm of ovary; Mammalian Oviducts; Mediator of activation protein; Medroxyprogesterone 17-Acetate; Modeling; Molecular; Molecular Analysis; Molecular Genetics; Mus; Mutation; Norethindrone; Ovarian; Ovary; Oxidative Stress; Oxidative Stress Pathway; PTEN gene; PTPRC gene; Paraffin; Pharmacology; Plasma; Postmenopause; Prevention; Prevention trial; Preventive; Primary Cell Cultures; Progesterone; Progestins; Protein p53; Proteins; RNA; Reactive Oxygen Species; Reproducibility; Role; S-Phase Fraction; Sampling; Secretory Cell; Serous; Stains; Surface; TNF gene; TP53 gene; Techniques; Testing; Time; Tube; Urokinase Plasminogen Activator Receptor; Vitamin D; Western Blotting; Woman; Work; analog; carcinogenesis; experimental study; fimbria; in vivo Model; monocyte; mortality; mouse model; mutant; ovarian cancer prevention; p53-binding protein 1; parent grant; response

Project Summary/Abstract In the early stages of ovarian carcinogenesis, it is now thought that the fimbria acquires molecular and genetic alterations when exposed to inflammatory mediators and associated oxidative stress (reactive oxygen species-ROS) released during ovulatory events from the adjacent ovary. These changes lead to the “p53 signature”- accumulation of mutant p53 protein (earliest genetic alteration in ovarian cancer), in the secretory cells of the fimbria ultimately leading to the development of serous tubal intraepithelial carcinoma (STIC), which spreads via shedding/exfoliation directly to the adjacent ovary and into the abdominal cavity. The p53 signatures and STIC lesions which evolve in an inflammatory, oxidative and DNA-toxic microenvironment are characterized by distinct features including loss of polarity, epithelial tufting, pleomorphic nuclei, abnormal p53 expression and a high-proliferative index. The discovery of these lesions and how they develop opens the door to the formulation of pharmacologic strategies that arrest and/or reverse the early transformative events in the fimbria, with immense potential to decrease ovarian cancer incidence and mortality through prevention. Previously, our work has focused primarily on the ovarian surface epithelium as the biologic target for ovarian cancer prevention using progestins and vitamin D. However, little is known regarding their biologic effects in the FTE. The objective of this study is to explore the impact of progestin and vitamin D on inflammation and oxidative stress in early carcinogenesis of ovarian cancer in in vitro and in vivo models of the disease. We hypothesize that inhibition of inflammatory and oxidative effects may comprise a biologic mechanism contributing to the cancer preventive effects of these agents. Furthermore, we will examine whether the combination of progestin and vitamin D is more effective than either agent alone. To test this hypothesis, we will utilize the following samples from the parent grant to evaluate inflammatory and oxidative stress pathways following administration of progestin and vitamin D: (1) cell cultures of primary FTE as well as transformed FTE harboring dominant negative mutant p53 obtained and established from pre- and postmenopausal women undergoing gynecologic surgery for benign indications, (2) paraffin sections of the fallopian tube and corresponding isolates (RNA, DNA, protein and plasma/serum) obtained from the mice (mogp-TAg and Dicer-PTEN) undergoing prevention trials with progestins and vitamin D.

项目总结/摘要 在卵巢癌发生的早期阶段，现在认为， 以及暴露于炎症介质和相关氧化应激时的遗传改变 （活性氧-ROS）在排卵事件期间从邻近卵巢释放。这些 这些变化导致“p53特征”-突变型p53蛋白的积累（最早的遗传标记）， 卵巢癌中的改变），在伞的分泌细胞中，最终导致 浆液性输卵管上皮内癌（STIC）的发展，通过 脱落/剥落直接到达相邻卵巢并进入腹腔。的p53 在炎症、氧化和DNA毒性的过程中演变的信号和STIC病变 微环境的特征在于不同的特征，包括极性丧失，上皮簇， 多形性核，异常p53表达和高增殖指数。的发现 这些病变以及它们如何发展为制定药理学策略打开了大门 阻止和/或逆转伞部的早期变革事件，具有巨大的潜力 通过预防降低卵巢癌的发病率和死亡率。 以前，我们的工作主要集中在卵巢表面上皮细胞作为生物靶点 使用孕激素和维生素D预防卵巢癌。然而，人们对 他们在FTE中的生物效应。本研究的目的是探讨 雷公藤多甙和维生素D对乳腺癌早期炎症和氧化应激的影响 卵巢癌的体外和体内疾病模型。我们假设抑制 炎症和氧化作用可能包括一种生物学机制， 这些药物的癌症预防作用。此外，我们将研究是否结合 维生素D和维生素D的组合比单独使用任何一种药物都更有效。为了验证这个假设，我们 将利用来自母基金的以下样本来评估炎症和氧化 在施用维生素D后应激途径：（1）原代细胞培养物 获得了FTE以及携带显性阴性突变体p53的转化FTE， 从绝经前和绝经后妇女接受妇科手术良性 适应症，（2）输卵管的石蜡切片和相应的分离物（RNA，DNA， 蛋白质和血浆/血清），其得自经历了以下过程的小鼠（mogp-TAg和Dicer-PTEN）： 孕激素和维生素D的预防试验。