PTTG Role in Ovarian Tumorigenesis and Matastasis

PTTG 在卵巢肿瘤发生和转移中的作用

• 批准号: 7179641
• 负责人: Sham S. Kakar
• 金额: $ 26.3万
• 依托单位: UNIVERSITY OF LOUISVILLE
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-03-26 至 2011-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7179641
• 关键词: 5q35.1; AKT Signaling Pathway; Address; Adenoviruses; Aneuploidy; Animal Model; Antineoplastic Agents; Base Sequence; Boxing; Cancer Model; Cause of Death; Cell Proliferation; Cells; Cessation of life; Chromosomal Instability; Chromosome abnormality; Chromosomes; Complementary DNA; Crossbreeding; Cytoplasm; Data; Detection; Developed Countries; Developing Countries; Development; Down-Regulation; Enzyme-Linked Immunosorbent Assay; Epithelial Cells; Epithelium; Fetal Kidney; Fetal Liver; Fibroblast Growth Factor 2; Gene Expression; Genes; Genetic; Genetically Engineered Mouse; Genomic Instability; Growth; Gynecologic; Health; Human; IL8 gene; In Vitro; Laboratories; Lead; Localized; Maintenance; Malignant Neoplasms; Malignant neoplasm of ovary; Mediating; Messenger RNA; Methods; Modeling; Molecular; Molecular Cloning; Molecular Target; Mus; Mutation; Neoplasm Metastasis; Nuclear; Nuclear Protein; Nuclear Proteins; Nude Mice; Oncogene Proteins; Oncogenes; Oncogenic; Ovarian; Ovarian Surface Epithelial-Stromal Tumor; Ovary; PI3K/AKT; PTTG1 gene; Phenotype; Polymerase Chain Reaction; Preclinical Testing; Prevention; Process; Production; Proline-Rich Domain; Protein Overexpression; Protein Sequence Analysis; Proteins; Rate; Reporting; Research Personnel; Role; Sister Chromatid; Sister Chromatid Exchange; Small Interfering RNA; Staging; Structure; Surface; System; Testis; Time; Transgenic Animals; Transgenic Mice; Tumor Suppression; United States; Vascular Endothelial Growth Factors; Woman; angiogenesis; base; c-myc Genes; cancer diagnosis; cell type; expression vector; gene function; human PTTG1 protein; human tissue; in vivo; indexing; knockout animal; loss of function; malignant breast neoplasm; metaplastic cell transformation; mortality; neoplastic; neoplastic cell; novel; ovarian neoplasm; pituitary tumor-transforming proteins; programs; promoter; small molecule; therapy development; tumor; tumor growth; tumor initiation; tumorigenesis; tumorigenic

DESCRIPTION (provided by applicant): Ovarian cancer is the fifth most commonly diagnosed cancer among women and the most frequent cause of death from gynecologic malignancies in the United States. Molecular mechanisms that initiate and support ovarian tumorigenesis are not well defined. We cloned a novel oncogene "PTTG" also known as securin from human testis and ovarian tumors and studied its function in tumorigenesis. PTTG is a multifunctional protein and is highly expressed in many tumors, including tumors of ovary. Introduction of PTTG into NIH3T3 and HEK293 cells induces cellular transformation and promotes tumor formation in nude mice, suggesting its strong oncogenic function. Notably, PTTG has been shown to inhibit separation of sister chromatids, and to increase the synthesis and secretion of bFGF, VEGF, and IL-8 as well as activate the expression of the oncogene, c-myc and PI3K/AKT signaling pathway, suggesting that the oncogenic activity of PTTG may involve induction of aneuploidy and chromosomal instability, increased angiogenesis, and production of growth promoting oncogene products. Down-regulation of PTTG expression in ovarian tumor cells in vitro and its deletion in animals (Knockout) results in reduction of tumor development, suggesting its important role in maintenance of cancer phenotype. The long-term objectives of this application are to understand the role of PTTG in ovarian tumorigenesis and validate PTTG as a molecular target for the development of anti- neoplastic agents. In this application we propose: i) to determine the effect of overexpression of PTTG in ovarian epithelial cells on cellular transformation and tumor development in nude mice; ii) to determine the effect of overexpression of PTTG in ovarian surface epithelial cells on ovarian tumor initiation, progression and metastasis in transgenic animals and determine mechanisms that support tumor growth and metastasis; and iii) to determine the effect of down-regulation of PTTG expression in ovarian tumor cells on tumor suppression and metastasis and determine mechanisms that lead to suppression of tumor growth and metastasis. These studies will provide critical information regarding the mechanisms of PTTG in ovarian tumorigenesis and metastasis and set up basis for the development of small molecules to inhibit PTTG function as anti-neoplastic agents. In addition transgenic animal model developed from our studies could enhance efforts aimed at developing new methods for detection, prevention, and treatment of ovarian cancer.

描述（由申请人提供）：卵巢癌是美国女性中第五大最常诊断的癌症，也是妇科恶性肿瘤最常见的死亡原因。启动和支持卵巢肿瘤发生的分子机制尚未明确。我们从人睾丸和卵巢肿瘤组织中克隆了一个新的癌基因PTTG，并研究了其在肿瘤发生中的作用。PTTG是一种多功能蛋白，在包括卵巢肿瘤在内的多种肿瘤中高度表达。将PTTG导入NIH 3 T3和HEK 293细胞中诱导细胞转化并促进裸鼠肿瘤形成，表明其具有强的致癌作用。值得注意的是，PTTG已显示出抑制姐妹染色单体的分离，并增加bFGF、VEGF和IL-8的合成和分泌，以及激活癌基因、c-myc和PI 3 K/AKT信号传导途径的表达，这表明PTTG的致癌活性可能涉及诱导非整倍性和染色体不稳定性、增加血管生成和产生生长促进癌基因产物。体外卵巢肿瘤细胞中PTTG表达的下调及其在动物中的缺失（敲除）导致肿瘤发展减少，表明其在维持癌症表型中的重要作用。本申请的长期目标是了解PTTG在卵巢肿瘤发生中的作用，并验证PTTG作为开发抗肿瘤剂的分子靶标。在本申请中，我们提出：i）确定PTTG在卵巢上皮细胞中的过表达对裸鼠中的细胞转化和肿瘤发展的影响; ii）确定PTTG在卵巢表面上皮细胞中的过表达对转基因动物中的卵巢肿瘤起始、进展和转移的影响，并确定支持肿瘤生长和转移的机制;和iii）确定卵巢肿瘤细胞中PTTG表达的下调对肿瘤抑制和转移的影响，并确定导致肿瘤生长和转移抑制的机制。这些研究将为PTTG在卵巢肿瘤发生和转移中的作用机制提供重要信息，并为开发抑制PTTG功能的小分子抗肿瘤药物奠定基础。此外，从我们的研究中开发的转基因动物模型可以加强旨在开发用于检测、预防和治疗卵巢癌的新方法的努力。