Prostate Cancer Metastasis Suppressor: Role of RKIP

前列腺癌转移抑制剂：RKIP 的作用

• 批准号: 6872148
• 负责人: Evan T Keller
• 金额: $ 25.09万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-04-01 至 2009-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6872148
• 关键词: SCID mouse; angiogenesis; apoptosis; biological signal transduction; cell line; cell proliferation; gene expression; kinase inhibitor; metastasis; neoplasm /cancer genetics; neoplastic process; oncogenes; serine threonine protein kinase; transfection; tumor suppressor genes; tumor suppressor proteins

DESCRIPTION (provided by applicant): Using a gene array, we have identified that expression of Raf kinase inhibitor protein (RKIP) is down-regulated in prostate cancer metastases. RKIP inhibits JAK/STAT activation and Raf-mediated activation of MEK/ERK. Immunohistochemistry confirmed that RKIP is present in normal prostate and primary prostate tumors, but absent in prostate cancer metastases. Furthermore, we have demonstrated that transfection of a metastatic prostate cancer cell line with RKIP cDNA prevents metastasis in a murine model while having no effect on growth rate of the primary tumor and transfection of a non-metastatic prostate cancer cell line with antisense RKIP promotes metastasis. Taken together, these data lead us to hypothesize RKIP is a prostate cancer metastasis-suppressor gene, whose loss promotes metastasis through MEK/ERK and JAK/STAT. To test our hypothesis, we will perform the following specific aims: 1. Determine the extent of RKIP's metastasis suppressor activity in vivo. Using several novel prostate cancer cell lines we will determine the effect of modulating RKIP levels on metastasis in murine models. 2. Identify the cellular mechanism(s) through which RKIP dysregulation promotes metastasis. We will evaluate the effect of manipulating RKIP levels on pro-metastatic parameters including angiogenesis, endothelial adhesion and invasiveness. Once we identify a target molecule based on these in vitro studies we will use inhibitors in vivo to determine if blocking these activities inhibits loss of RKIP-mediated metastasis. 3.Determine the signaling pathways through which decreased RKIP expression mediates metastasis. We will evaluate the effects of modulating the activities of the JAK/STAT and MEK signaling pathways on in vitro parameters including invasion, proliferation and apoptosis. Subsequently, we will determine the effect on establishment of metastases in vivo. Furthermore, we will determine if any pro-metastatic cellular phenotypes identified in Aim 2 are modulated by these signaling pathways. when completed, we hope this work will lead to a better understanding of the mechanisms through which RKIP suppresses metastasis and hopefully identify specific targets to inhibit metastasis.

描述(申请人提供)：利用基因阵列，我们发现Raf激酶抑制蛋白(RKIP)在前列腺癌转移中表达下调。RKIP抑制JAK/STAT激活和Raf介导的MEK/ERK激活。免疫组织化学证实RKIP在正常前列腺和原发前列腺癌中表达，而在前列腺癌转移瘤中不表达。此外，我们还证明，在小鼠模型中，转移性前列腺癌细胞系RKIP基因的转染可防止转移，而对原发肿瘤的生长速度无影响，而反义RKIP基因转染非转移性前列腺癌细胞系可促进肿瘤转移。综上所述，这些数据使我们假设RKIP是一个前列腺癌转移抑制基因，其缺失通过MEK/ERK和JAK/STAT促进转移。为了验证我们的假设，我们将执行以下具体目标：1.确定RKIP在体内的转移抑制活性的程度。利用几个新的前列腺癌细胞系，我们将确定调节RKIP水平对小鼠模型转移的影响。2.明确RKIP异常促进肿瘤转移的细胞机制(S)。我们将评估控制RKIP水平对促转移参数的影响，包括血管生成、内皮黏附和侵袭性。一旦我们根据这些体外研究确定了目标分子，我们将在体内使用抑制剂来确定阻断这些活性是否可以抑制RKIP介导的转移的丢失。3.确定RKIP表达降低介导肿瘤转移的信号通路。我们将评估调节JAK/STAT和MEK信号通路的活性对体外侵袭、增殖和凋亡等参数的影响。随后，我们将确定其对体内转移建立的影响。此外，我们将确定在AIM 2中发现的任何促转移细胞表型是否受到这些信号通路的调节。完成后，我们希望这项工作将导致更好地理解RKIP抑制转移的机制，并有望确定抑制转移的特定靶点。