Project 2: Fetuin-A in Prostate Cancer

项目 2：胎球蛋白-A 在前列腺癌中的作用

• 批准号: 10327838
• 负责人: Xiaofei Wang
• 金额: $ 0.43万
• 依托单位: TENNESSEE STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-23 至 2026-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10327838
• 关键词: 1-Phosphatidylinositol 3-Kinase; 3-Dimensional; AKT Signaling Pathway; Ablation; Address; Affect; African American; American; Androgens; Attenuated; Biogenesis; Biological Markers; Cancer Etiology; Cells; Cessation of life; Data; Death Rate; Disease; Disease Outcome; Doctor of Philosophy; Enterobacteria phage P1 Cre recombinase; Female; Freezing; Generations; Genes; Gleason Grade for Prostate Cancer; Glycoproteins; Growth; Human; Immunohistochemistry; In Vitro; Indolent; Knock-out; Knockout Mice; LNCaP; Laboratories; Lead; Linear Regressions; Malignant neoplasm of prostate; Mediating; Messenger RNA; Mitogen-Activated Protein Kinases; Modeling; Molecular; Mus; Mutant Strains Mice; Neoplasm Metastasis; Null Lymphocytes; PTEN gene; Patient-Focused Outcomes; Patients; Pharmaceutical Preparations; Play; Process; Production; Prognosis; Prognostic Marker; Prostate; Prostate Cancer therapy; Prostatic Neoplasms; Proteins; Proto-Oncogene Proteins c-akt; Puberty; Refractory; Regression Analysis; Research Personnel; Role; Serum; Signal Pathway; Signal Transduction; TLR4 gene; The Vanderbilt-Ingram Cancer Center at the Vanderbilt University; Tissues; Transfection; Tumor Volume; Western Blotting; Xenograft procedure; alpha-Fetoproteins; calcification; cancer health disparity; cancer initiation; cancer prevention; castration resistant prostate cancer; caucasian American; cell growth; cell motility; exosome; experimental study; in vivo; mRNA Expression; male; men; mouse model; mutant; nano-string; overexpression; probasin; prostate cancer cell; prostate cancer cell line; prostate cancer model; prostate cancer progression; tumor; tumor growth; tumor initiation; tumor progression; tumorigenic; uptake

PROJECT SUMMARY: FULL PROJECT 2 Even though the growth of prostate cancer (PCa) is largely driven by androgens, a subset usually develops that is refractory to androgen ablation (also known as castration resistant PCa; CRPC) with potential for metastasis. Preliminary data from our laboratory has implicated fetuin-A, also known as alpha 2-Heremans-Schmid glycoprotein (AHSG), in the growth of PCa cells and in the production of “uptake-competent” exosomes. The objective of the proposed studies is to define the role and significance of fetuin-A in prostate cancer progression. We hypothesize that PCa cells express ectopic fetuin-A which is secreted and taken up by the cells via TLR4 to mediate the biogenesis of `uptake-competent' exosomes that promote PCa growth via activation of pAKT/pERK; moreover, we postulate that elevated fetuin-A expression serves as a prognostic biomarker for PCa. Three specific aims are proposed: Aim 1. To determine if fetuin-A expression is higher in AA PCa tissues relative to Caucasian American (CA) PCa tissues and whether high fetuin-A expression is associated with high Gleason Scores (>6) and enhanced pAKT and pERK. We will analyze mRNA expression of fetuin-A using NanoString as well as pAKT/pERK protein levels using immunohistochemistry (IHC) analysis of human PCa tissues. Multivariable linear regression analysis will be used to determine the correlation between fetuin-A, pAKT, pERK and Gleason scores in PCa tissues of AA and CA patients, as well as other progression parameters such as positive margins and spread of PCa. It is expected that fetuin-A, pAKT and pERK will be expressed at high levels in PCa tissues of AA patients particularly those with high Gleason scores (>6). Aim 2. To determine the role of ectopic fetuin-A in exosome biogenesis, promotion of 2-D and 3-D growth, motility and invasive capacity of PCa cells. In this aim, we will overexpress and knockout fetuin-A in two PCa cell lines to determine whether fetuin-A plays a causal role in the biogenesis of `uptake competent' exosomes that transmit growth signals in recipient cells. We expect to demonstrate that exosomes from fetuin-A overexpressing cells will promote 2-D, 3-D growth and motility and invasion of PCa cells while exosomes from fetuin-A null cells will not. Aim 3. To investigate the efficacy of targeting fetuin-A mediated signaling on the suppression of prostate tumor initiation and growth in mice. In this aim, we will utilize the Pten-null mouse model for PCa to determine whether Pten loss requires intact fetuin-A gene to mediate its tumorigenic role and whether loss of fetuin-A in Pten-/-/fetuin-A-/- double mutant mice attenuates the tumorigenic role of Pten-null. We expect reduced tumor growth in the double mutant mice compared to Pten-null fetuin-A+/+ mice. Significance: There is an urgent need to identify biomarkers that can differentiate CRPC from indolent PCa and this proposal addresses that need and evaluates the process by which fetuin-A enhances PCa tumor growth.

项目摘要：完整项目2 即使前列腺癌的生长（PCA）在很大程度上是由雄激素驱动的，但该子集通常会发展出来 对雄激素消融（也称为耐cantatration PCA; CRPC）具有耐受性，具有转移的潜力。 我们实验室的初步数据已经实施了fetuin-a，也称为alpha 2- heremans-schmid 糖蛋白（AHSG），PCA细胞的生长以及“吸收能力”外泌体的产生。 拟议的研究的目的是定义fetuin-a在前列腺癌进展中的作用和意义。 我们假设PCA细胞表达Ecopic fetuin-A，该f ecopic fe to to to to to to to to to to copic fetuin-a。 调解通过激活PAKT/PERK促进PCA生长的“吸收能力”外泌体的生物发生； 此外，我们假设升高的fetuin-A表达是PCA的预后生物标志物。三 提出了具体目的：目标1。确定AA PCA组织相对的Fetuin-A表达是否较高 高加索美式（CA）PCA组织，以及高胎儿A的表达是否与高有关 格里森分数（> 6）和增强的PAKT和PERK。我们将使用fetuin-a的mRNA表达 使用免疫组织化学（IHC）分析人PCA 组织。多变量线性回归分析将用于确定fetuin-a，pakt， AA和CA患者的PCA组织中的PERK和GLEASON分数以及其他进展参数此类 作为正缘和PCA的传播。预计fetuin-a，pakt和perk将在高处表达 AA患者的PCA组织中的水平，尤其是Gleason评分高的患者（> 6）。目标2。确定 Ecopic Fetuin-A在外泌体生物发生，促进2-D和3-D生长，运动和侵入性的作用 PCA细胞的容量。在此目的中，我们将在两个PCA细胞系中过表达和敲除胎儿A以确定 Fetuin-A是否在传播生长的“摄取效果”外泌体的生物发生中起因果作用 受体单元中的信号。我们希望证明来自fetuin-a过表达细胞的外泌体将 促进2-D，3-D生长和运动能力以及PCA细胞的侵袭，而fetuin-A无效细胞的外泌体不会。 目标3。研究靶向fetuin-a介导的信号在抑制前列腺的效率 小鼠的肿瘤启动和生长。在此目标中，我们将利用PTEN-NULL鼠标模型来确定 PTEN损失是否需要完整的Fetuin-A基因介导其肿瘤性作用以及fetuin-a的丧失是否 pten - / - /fetuin-a - / - 双重突变小鼠减弱了pten-null的致瘤作用。我们预计肿瘤减少 与pten-null fetuin-a+/+小鼠相比，双突变小鼠的生长。意义：迫切需要 确定可以将CRPC与顽固的PCA区分开的生物标志物，该提案解决了需要和 评估Fetuin-A增强PCA肿瘤生长的过程。