Mechanism of DLC1-mediated tumor suppression

DLC1介导的肿瘤抑制机制

基本信息

批准号：
8103266
负责人：
SU HAO LO
金额：
$ 30.88万
依托单位：
UNIVERSITY OF CALIFORNIA AT DAVIS
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-07-01 至 2015-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8103266
关键词：
Acute Adhesions Animals Attenuated B-Lymphocytes Biological Process Breast Cause of Death Cell Adhesion Cell Culture System Cell Shape Cell physiology Cells Colon Colon Carcinoma DNA Methylation Data Development Disease Epithelial Cells Event Focal Adhesions Generations Genomics Goals Health In Vitro Investigation Kidney Knock-out Knockout Mice Knowledge Link Lipids Lung Malignant Neoplasms Malignant neoplasm of liver Malignant neoplasm of prostate Mediating Methods Modeling Molecular Mus Mutation Neoplasm Metastasis Ovary PTEN gene Pathway interactions Prevention Primary carcinoma of the liver cells Prostate Prostatic Neoplasms Proteins Regulation Research Risk Role SAM Domain Signal Pathway Stomach Stream Tertiary Protein Structure Testing Therapeutic Tumor Angiogenesis Tumor Cell Invasion Tumor Suppression Tumor Suppressor Genes Tumor Suppressor Proteins Tumorigenicity United States Uterus Vascular Endothelial Growth Factors angiogenesis anticancer research cancer type cell growth cell motility clinically relevant men migration mouse model neoplastic cell novel prevent protein activation public health relevance therapeutic target tumor progression tumorigenesis

项目摘要

DESCRIPTION (provided by applicant): Deleted in liver cancer 1 (DLC1) is a focal adhesion protein that contains multiple domains including SAM (sterile alpha motif), RhoGAP (RhoGTPase activation protein), and START (steroidogenic acute regulatory (StAR)-related lipid transfer). It was originally isolated as a potential tumor suppressor gene often deleted in hepatocellular carcinoma. Further studies have indicated that down-expression of DLC1 either by genomic deletion or DNA methylation is associated with a variety of cancer types including prostate, lung, breast, kidney, colon, uterus, ovary, and stomach. Mutations in DLC1 that attenuate its expression and function have been identified in prostate and colon cancer. Numerous in vitro data have linked many of DLC1's biological function to its negative regulation of the RhoA pathway through DLC1's RhoGAP domain. On the other hand, the focal adhesion localization is also essential for DLC1's function in suppression of tumor cell growth. Although the critical role of RhoGAP domain on DLC1's function is established, the roles of other domains and novel function of DLC1 are not well studied. In addition, the mechanisms underlying DLC1-mediated tumor suppression in cell culture systems and in an animal remain to be established. We hypothesize that DLC1 is a tumor suppressor that regulates cellular events including cell adhesion, migration, and angiogenesis through its multiple domains; and that loss of its expression or function increases the risk for prostate cancer. The overall goal of this proposal is to systematically determine the domain function of DLC1 and elucidate the molecular mechanisms; to investigate novel functions of DLC1, such as its role in angiogenesis; and to demonstrate its role as a tumor suppressor in the prostate of a mouse and develop better mouse models for prostate cancer, which is the second leading cause of death among men in the United States. There are specific aims to test our hypothesis: Specific Aim 1. Investigation of the molecular mechanism how DLC1 regulates cell shape, adhesion, migration, and tumorigenicity Specific Aim 2. Discovery of new function(s) of DLC1 in preventing prostate cancer development Specific Aim 3. Demonstration of the role of DLC1 in mouse prostate tumorigenesis and establishment of prostate cancer mouse models The results of the proposed studies will contribute significantly to knowledge of the function of DLC1 and molecular mechanisms involved, and provide new ideas and therapeutic approaches for prostate cancer and other cancers that are associated with the loss of DLC1. PUBLIC HEALTH RELEVANCE: Relevance This research is directed toward understanding the mechanism of DLC1-mediated tumor suppression in prostate cancer. Providing evidence for DLC1 contributions to prevention of prostate tumor progression is a prelude to developing methods for therapeutic targeting of its associated pathways. The knowledge may apply to other cancers, since loss of DLC1 is associated with a variety of cancer types.

描述（申请人提供）：肝癌删除1（DLC1）是一种粘着斑蛋白，含有多个结构域，包括SAM（无菌α基序）、RhoGAP（RhoGTP酶激活蛋白）和START（类固醇生成急性调节（StAR）相关蛋白）脂质转移）。它最初被分离为一种潜在的肿瘤抑制基因，经常在肝细胞癌中被删除。进一步的研究表明，通过基因组缺失或 DNA 甲基化导致的 DLC1 下调表达与多种癌症类型相关，包括前列腺癌、肺癌、乳腺癌、肾癌、结肠癌、子宫癌、卵巢癌和胃癌。在前列腺癌和结肠癌中已发现 DLC1 的突变会削弱其表达和功能。大量体外数据已将 DLC1 的许多生物学功能与其通过 DLC1 的 RhoGAP 结构域对 RhoA 通路的负调节联系起来。另一方面，粘着斑定位对于DLC1抑制肿瘤细胞生长的功能也至关重要。尽管 RhoGAP 结构域对 DLC1 功能的关键作用已被确立，但其他结构域的作用和 DLC1 的新功能尚未得到很好的研究。此外，细胞培养系统和动物体内 DLC1 介导的肿瘤抑制机制仍有待确定。我们假设 DLC1 是一种肿瘤抑制因子，通过其多个域调节细胞事件，包括细胞粘附、迁移和血管生成；并且其表达或功能的丧失会增加患前列腺癌的风险。该提案的总体目标是系统确定DLC1的域功能并阐明其分子机制；研究 DLC1 的新功能，例如其在血管生成中的作用；证明其在小鼠前列腺中作为肿瘤抑制因子的作用，并开发更好的前列腺癌小鼠模型，前列腺癌是美国男性第二大死亡原因。有具体目标来检验我们的假设：具体目标 1. 研究 DLC1 如何调节细胞形状、粘附、迁移和致瘤性的分子机制具体目标 2. 发现 DLC1 在预防前列腺癌发展中的新功能具体目标3. 证实DLC1在小鼠前列腺肿瘤发生中的作用以及前列腺癌小鼠模型的建立本研究的结果将极大地有助于了解DLC1的功能和所涉及的分子机制，并提供新的研究方向。针对前列腺癌和其他与 DLC1 缺失相关的癌症的想法和治疗方法。公共卫生相关性：相关性本研究旨在了解 DLC1 介导的前列腺癌肿瘤抑制机制。为 DLC1 对预防前列腺肿瘤进展的贡献提供证据是开发针对其相关通路的治疗靶向方法的前奏。这些知识可能适用于其他癌症，因为 DLC1 的缺失与多种癌症类型相关。