Role of Cten in Prostate Cancer

Cten 在前列腺癌中的作用

基本信息

批准号：
8448261
负责人：
SU HAO LO
金额：
$ 22.66万
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：
2004
资助国家：
美国
起止时间：
2004-04-01 至 2016-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8448261
关键词：
17q21 Actins American Androgen Receptor Androgens Animals Apoptosis Binding Biological C-terminal Cancer Patient Cell Adhesion Cell Adhesion Molecules Cell Nucleus Cell surface Cells Chromosomes Colon Colon Carcinoma Complex Cytoskeleton Development Disease Endothelial Cells Event Focal Adhesions Gene Expression Genes Genetic Health Histocompatibility Testing Human Integrins Knowledge Malignant - descriptor Malignant Neoplasms Malignant neoplasm of liver Malignant neoplasm of prostate Mediating Modality Modeling Molecular Mus Nuclear Nuclear Translocation Oncogenic Pathway interactions Phosphatidylinositol 4,5-Diphosphate Phosphoric Monoester Hydrolases Phosphorylation Phosphotransferases Play Preclinical Drug Evaluation Prostate Prostatic Protein Kinase Proteins Receptor Signaling Recruitment Activity Regulation Reporting Research Risk Role Serine Signal Transduction Solid System Testing Tissues Transducers Tumor Promoters Tumor Suppression Tumor Suppressor Proteins Vascular Endothelial Growth Factors Work angiogenesis anticancer research cancer type caspase-3 cell motility cell transformation cell type clinically relevant in vivo men migration mouse model new therapeutic target novel marker overexpression prevent prostate cancer cell prostate cancer model prostate carcinogenesis rho tensin therapeutic target tumor tumorigenesis

项目摘要

DESCRIPTION (provided by applicant): Prostate cancer is the most common malignancy in North American men. However, the genetic events associated with the malignant transformation of prostatic cells are largely unknown. Identification of new prostate specific genes could provide new markers and could be instrumental for development of new treatment modalities. Cten (C-terminal tensin-like) is a new focal adhesion molecule, whose expression is relatively restricted at the normal prostate gland. We have reported that cten is absent or down-regulated in prostate cancers, is a target of caspase 3 and an effector during apoptosis, regulates cell migration, recruits a tumor suppressor, DLC1 (deleted in liver cancer 1), to focal adhesions and this interaction is critical for DLC1's tumor suppression activity. Interestingly, cten localizes not only to focal adhesions but also in the nucleus, suggesting that cten may be a transducer molecule, possibly involved in nuclear events in addition to events at the cell surface. Human cten gene is located on chromosome 17q21, a region often deleted in prostate cancer. These studies suggest that cten is a prostate-specific tumor suppressor whose disruption has repercussions in prostate cancer. However, our recent studies have shown that although not normally expressed in other tissues, cten is overexpressed in a large number of colon cancer patients, indicating that cten may possess an oncogenic activity in the colon. Therefore, cten may have dual functions that are tissue type specific. In this renewal proposal we will continually investigate the role of cten in the prostate and offer a molecular mechanism for the seemingly contradictory function of cten in colon cancer. We hypothesize that cten is a prostate-specific tumor suppressor that plays important roles at the focal adhesions and in the nucleus; and that alteration of cten expression/ function disrupts its normal actions and increases the risk for prostate cancer. Three specific aims are proposed to test our hypothesis. Aim 1. To determine the role of cten in regulating the tumor suppression activity of DLC1 Aim 2. To establish the mechanism of cten nuclear translocation and its role in tumorigenesis Aim 3. To demonstrate the function of cten in prostate tumorigenesis using in vivo systems The gene to be studied is a very unique molecule, a focal adhesion-nucleus protein that may regulate the DLC1 tumor suppressor at focal adhesions and mediate a crosstalk between Wnt and androgen signaling in the nucleus. Verification of our hypothesis would indicate a possible role for cten as a novel therapeutic target for prostate cancer and maybe other cancer types as well. Our animal studies will reveal cten's in vivo function and provide better mouse prostate cancer models for studying prostate tumorigenesis and drug screening.

描述（由申请人提供）：前列腺癌是北美男性最常见的恶性肿瘤。然而，与前列腺细胞恶性转化相关的遗传事件在很大程度上尚不清楚。新的前列腺特异性基因的鉴定可以提供新的标记，并且有助于开发新的治疗方式。 Cten（C端张力蛋白样）是一种新的粘着斑分子，其表达相对限制在正常前列腺中。我们已经报道，cten 在前列腺癌中缺失或下调，是 caspase 3 的靶标和细胞凋亡过程中的效应子，调节细胞迁移，招募肿瘤抑制因子 DLC1（在肝癌 1 中删除），以促进粘着斑，这相互作用对于 DLC1 的肿瘤抑制活性至关重要。有趣的是，cten 不仅定位于粘着斑，而且定位于细胞核，这表明 cten 可能是一种转导分子，除了细胞表面的事件外，可能还参与核事件。人类cten基因位于染色体17q21上，该区域在前列腺癌中经常被删除。这些研究表明 cten 是一种前列腺特异性肿瘤抑制因子，其破坏会对前列腺癌产生影响。然而，我们最近的研究表明，虽然cten在其他组织中不正常表达，但在大量结肠癌患者中过度表达，表明cten可能在结肠中具有致癌活性。因此，cten 可能具有组织类型特异性的双重功能。在这个更新提案中，我们将继续研究 cten 在前列腺中的作用，并为 cten 在结肠癌中看似矛盾的功能提供分子机制。我们假设 cten 是一种前列腺特异性肿瘤抑制因子，在粘着斑和细胞核中发挥重要作用； cten 表达/功能的改变会破坏其正常作用并增加患前列腺癌的风险。提出了三个具体目标来检验我们的假设。目的1.确定cten在调节DLC1肿瘤抑制活性中的作用目的2.建立cten核转位机制及其在肿瘤发生中的作用目标 3. 使用体内系统证明 cten 在前列腺肿瘤发生中的功能待研究的基因是一种非常独特的分子，是一种粘着斑核蛋白，可以调节粘着斑处的 DLC1 肿瘤抑制因子，并介导细胞核中 Wnt 和雄激素信号传导之间的串扰。我们的假设的验证将表明 cten 作为前列腺癌以及其他癌症类型的新治疗靶点的可能作用。我们的动物研究将揭示cten的体内功能，并为研究前列腺肿瘤发生和药物筛选提供更好的小鼠前列腺癌模型。