Mechanism of tumor metastases suppression by Drg1

Drg1抑制肿瘤转移的机制

基本信息

批准号：
7483667
负责人：
Kounosuke Watabe
金额：
$ 17.34万
依托单位：
SOUTHERN ILLINOIS UNIVERSITY SCH OF MED
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-09-01 至 2012-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7483667
关键词：
Acceleration Affect Animal Experiments Animal Model Animals Biological Process Cancer Patient Cell Line Cells Clinical Clinical Data Complex Data Diagnosis Diagnostic Disease Down-Regulation Genes Goals Hybrids Immunohistochemistry In Vitro KAI1 gene Localized Malignant neoplasm of lung Malignant neoplasm of prostate Malignant neoplasm of urinary bladder Mammary gland Medical Technology Metastasis Suppression Metastasis Suppressor Genes Metastatic Prostate Cancer Molecular Mus Neoplasm Metastasis Organ Other Body Part Pathway interactions Patients Pattern Prostate Prostatic Neoplasms Purpose Research Personnel Role SCID Mice Sampling Series Signal Transduction Signaling Molecule Small Interfering RNA Specimen Testing Transgenic Animals Tumor Cell Invasion Tumor Suppressor Proteins Tumorigenicity Tyrosine Phosphorylation United States Xenograft Model cancer diagnosis design gene repression in vivo knock-down lipoprotein receptor-related protein 6 men neoplastic cell novel strategies prognostic programs promoter research study tumor tumor progression tumorigenesis

项目摘要

DESCRIPTION (provided by applicant): Prostate cancer is the most frequently diagnosed cancer among men in the United States, exceeding lung cancer by a narrow margin. Once prostate cancer is diagnosed, the most critical question is whether the disease is localized or it has already metastasized to other parts of the body. Unfortunately, none of the current medical technologies "cure" the metastatic disease, and the patients who have acquired metastatic prostate cancer have dismal chance of survival. Therefore, there is an urgent need for developing a novel approach of target-specific therapy to metastatic tumor cells, which requires more comprehensive understanding of the molecular mechanism of metastases. We have recently found that Drg1 acts as a tumor metastases suppressor in prostate cancer. Ample evidence from both clinical data and the results of in vitro as well as animal experiments overwhelmingly support the notion that Drg1 is a metastasis suppressor gene and that the down-regulation of the gene results in acceleration of tumor metastasis. The most crucial question is how Drg1 suppresses the tumor metastases. Our key discoveries in investigating this question are four folds: (i) interacts with Wnt receptor, LRP6, (ii) activates Wnt suppressor, GSK3(3, (iii) suppresses Akt activity, (iv) down-modulates the expression of the metastases promoter, ATF3, and (v) up-regulates the expression of the metastases suppressor gene KAI1 through ATF3 down-regulation. Therefore, we propose to test our hypothesis that Drg1 interacts with LRP6 leading to activation of GSK30 by tyrosine phosphorylation and also de-phosphorylates Akt which together results in blockade of the Wnt pathway (Hypothesis 1), and that this inactivation of the Wnt pathway suppresses the expression of the metastases promoting gene, ATF3, followed by down regulation of KAI1 (Hypothesis 2). Specific aim 1 is designed to test whether Drg-1 suppresses tumor cell invasion by blocking the Wnt pathway via interaction with LRP6 and following GSK3? activation in vitro. The purpose of the Specific aim 2 is to clarify how the interaction between Drg1 and LRP6 leads to metastasis suppression in animal models. In Specific aim 3, we will examine the status of expression of the Wnt signal molecules and Drg1 in clinical specimens from prostate cancer patients. The objective of Specific aim 4 is to examine whether Drg1 controls the KAI1 expression via Wnt pathway in vitro and in vivo. Our long-term goal is to elucidate the molecular mechanism of suppressor function of the Drg-1 gene in tumor progression and also to establish diagnostic/prognostic value of the Drg-1 pathway for prostate cancer. We believe that the results of the proposed experiments will provide fundamental information to accomplish our ultimate goal, the control of tumor metastasis in cancer patients.

描述（由申请人提供）：前列腺癌是美国男性中最常诊断出的癌症，以微弱优势超过肺癌。一旦诊断出前列腺癌，最关键的问题是该疾病是局部的还是已经转移到身体的其他部位。不幸的是，目前的医疗技术都没有“治愈”转移性疾病，而患有转移性前列腺癌的患者生存机会渺茫。因此，迫切需要开发针对转移性肿瘤细胞的靶向特异性治疗的新方法，这需要更全面地了解转移的分子机制。我们最近发现 Drg1 在前列腺癌中充当肿瘤转移抑制剂。来自临床数据以及体外和动物实验结果的大量证据压倒性地支持Drg1是一种转移抑制基因并且该基因的下调会导致肿瘤转移加速的观点。最关键的问题是 Drg1 如何抑制肿瘤转移。我们研究这个问题的关键发现有四个方面：(i) 与 Wnt 受体 LRP6 相互作用，(ii) 激活 Wnt 抑制子，GSK3(3，(iii) 抑制 Akt 活性，(iv) 下调转移瘤的表达(v) 通过下调 ATF3 上调转移抑制基因 KAI1 的表达，因此，我们建议检验 Drg1 的假设。与 LRP6 相互作用，通过酪氨酸磷酸化激活 GSK30，并使 Akt 去磷酸化，共同导致 Wnt 通路的阻断（假设 1），并且 Wnt 通路的这种失活抑制了转移促进基因 ATF3 的表达，随后下调 KAI1（假设 2），旨在测试 Drg-1 是否通过阻断 Wnt 来抑制肿瘤细胞侵袭。具体目标 2 的目的是阐明 Drg1 和 LRP6 之间的相互作用如何导致动物模型中的转移抑制。在具体目标 3 中，我们将检查前列腺癌患者临床标本中 Wnt 信号分子和 Drg1 的表达状态。具体目标4的目的是检查Drg1是否在体外和体内通过Wnt途径控制KAI1的表达。我们的长期目标是阐明 Drg-1 基因抑制功能在肿瘤进展中的分子机制，并建立 Drg-1 通路对前列腺癌的诊断/预后价值。我们相信，所提出的实验结果将为实现我们的最终目标（控制癌症患者的肿瘤转移）提供基础信息。