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: 7754388
• 负责人: Sham S. Kakar
• 金额: $ 25.31万
• 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/7754388
• 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; 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; 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; Preclinical Testing; Prevention; Process; Production; Proline-Rich Domain; Protein Sequence Analysis; Proteins; 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; overexpression; pituitary tumor-transforming proteins; programs; promoter; small molecule; therapy development; tumor; tumor growth; tumor initiation; tumorigenesis; tumorigenic

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.

卵巢癌是女性中第五大最常诊断的癌症，也是最常见的原因