Vav3 Oncogene in Prostate Cancer

前列腺癌中的 Vav3 癌基因

• 批准号: 7490021
• 负责人: SHAN LU
• 金额: $ 26.68万
• 依托单位: UNIVERSITY OF CINCINNATI
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-08-28 至 2012-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7490021
• 关键词: Ablation; Androgen Receptor; Androgens; Animal Model; Attenuated; Cancer Etiology; Cancer Model; Cessation of life; Clinical Research; DH Domain; DNA; Detection; Development; Disease; Elevation; Epithelium; Gleason Grade for Prostate Cancer; Glutathione S-Transferase; Growth; Guanine Nucleotide Exchange Factors; Hormones; Malignant neoplasm of prostate; Mass Spectrum Analysis; Mediating; Microarray Analysis; Modality; Molecular; Mus; Nucleotides; Numbers; Oligonucleotide Microarrays; Oncogenes; Operative Surgical Procedures; Pathologic; Pathway interactions; Patients; Principal Investigator; Prostate; Prostatic Intraepithelial Neoplasias; Prostatic Neoplasms; Protein Overexpression; Proteins; Proteomics; Receptor Activation; Receptor Signaling; Role; Signal Pathway; Signal Transduction; Specimen; Staging; Stimulus; Techniques; Testing; Therapeutic; Transducers; Transgenic Mice; United States; androgen independent prostate cancer; base; cancer cell; cell growth; extracellular; hormone refractory prostate cancer; improved; men; mouse model; novel; pre-clinical; preclinical study; programs; receptor function; rho; rho GTP-Binding Proteins; tumor growth; tumor progression; young adult

DESCRIPTION (provided by applicant): Elevated androgen receptor (AR) activity and PI3K-Akt signaling are involved in prostate cancer development and progression. The mechanisms responsible for elevation of these two key signaling pathways in prostate cancer, however, have not fully elucidated. We found that Vav3 oncogene, a quanine nucleotide exchange factor (GEF) for Rac/Rho GTPases, is overexpressed in androgen-independent prostate cancer cells and in 32% of human prostate cancer. Further analysis revealed that Vav3 stimulates growth of prostate cancer cells, interacts with AR via the DH domain, and activates AR as a coactivator. Vav3, as a signal transducer, also upregulates PI3K-Akt signaling leading to AR activation. Furthermore, targeted overexpression of Vav3 in the prostate epithelium induces prostatic intraepithelial neoplasia (mPIN) in young adult mice as early as two months old. We hypothesize that overexpression of Vav3 inappropriately activates AR and promotes prostate cancer development and that further elevated Vav3 activity stimulates prostate cancer progression to the androgen-independent status. Three Specific Aims are proposed to test the hypothesis. Specific Aim 1: To determine the role of Vav3 overexpression in prostate cancer development and progression to the androgen-independent status in mouse prostate cancer models. We will investigate whether forced overexpression of Vav3 stimulates androgen-independent growth in prostate tumor and whether targeted overexpression of Vav3 in the prostate epithelium induces prostate cancer development and stimulates progression to the androgen-independent status in transgenic mice. Specific Aim 2: To elucidate the signaling pathways of Vav3 in prostate cancer. We will determine the underlying molecular mechanisms of Vav3 coactivation for AR and Vav3 signaling via the conventional Vav3-Rho-PI3K-Akt pathway leading AR activation in prostate cancer cells. We will also build up the whole Vav3-mediated signaling pathways that connect extracellular stimuli to AR signaling axis as well as cell growth and survival pathway by GST-pull down and Mass Spectrometry-based proteomics analysis. Specific Aim 3: To associate Vav3 overexpression with Gleason score, pathologic stage, PI3K-Akt signaling, and androgen-independent status in human prostate cancers. Once completed, these studies from the preclinical mouse model to the clinical study in human prostate cancer specimens will further our understanding of the mechanisms of prostate cancer development and its androgen-independent growth and provide targets and animal models for the rational development of novel therapies against prostate cancer.

描述（由申请人提供）：雄激素受体（AR）活性升高和PI3K-AKT信号传导参与前列腺癌的发展和进展。但是，导致前列腺癌中这两种关键信号通路升高的机制尚未完全阐明。我们发现，RAC/RHO GTPases的Quanine核苷酸交换因子（GEF）VAV3癌基因在雄激素非依赖性的前列腺癌细胞中过表达，在32％的人类前列腺癌中。进一步的分析表明，VAV3刺激前列腺癌细胞的生长，通过DH结构域与AR相互作用，并激活AR作为共激活剂。 VAV3作为信号传感器，也上调了导致AR激活的PI3K-AKT信号传导。此外，在前列腺上皮中有针对性的VAV3过表达会诱导前列腺内肿瘤（MPIN）在年轻的成年小鼠中早于两个月大。我们假设VAV3的过表达不恰当地激活AR并促进前列腺癌的发展，并进一步升高VAV3活性会刺激前列腺癌的进展到雄激素非依赖性的状态。提出了三个特定目标来检验该假设。具体目的1：确定VAV3过表达在小鼠前列腺癌模型中与雄激素非依赖性状态的发展中的作用。我们将调查VAV3的过度表达是否刺激前列腺肿瘤中雄激素非依赖性的生长以及在前列腺上皮中靶向VAV3的过表达是否会诱导前列腺癌的发展并刺激转基因小鼠中雄激素独立的状态。特定目标2：阐明前列腺癌中VAV3的信号传导途径。我们将通过常规的VAV3-RHO-PI3K-AKT途径确定VAV3共激活的基本分子机制，用于AR和VAV3信号传导，导致前列腺癌细胞中AR激活。我们还将建立整个VAV3介导的信号通路，这些信号通路将细胞外刺激与AR信号轴以及基于GST-PULL的基于GST-PULL和基于质谱的蛋白质组学分析连接到AR信号轴以及细胞生长和存活途径。特定目标3：将VAV3的过表达与格里森评分，病理阶段，PI3K-AKT信号传导和人类前列腺癌中无关的状态相关联。完成后，这些研究从临床前小鼠模型到人类前列腺癌标本的临床研究将进一步了解我们对前列腺癌发展机制及其与雄激素无关的生长的机制，并为针对前列腺癌的新型疗法提供了靶标和动物模型。