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.

卵巢癌是女性中最常见的癌症的第五种，也是最常见的原因 美国妇科恶性肿瘤死亡。启动和支持的分子机制 卵巢肿瘤发生尚未很好地定义。我们克隆了一种新颖的癌基因“ PTTG”，也称为Secuin 人睾丸和卵巢肿瘤，研究了其在肿瘤发生中的功能。 PTTG是一种多功能蛋白 并且在许多肿瘤中高度表达，包括卵巢肿瘤。将PTTG引入NIH3T3和 HEK293细胞诱导细胞转化并促进裸鼠的肿瘤形成，表明其 强大的致癌功能。值得注意的是，PTTG已被证明可以抑制姐妹染色单体的分离，并抑制 增加BFGF，VEGF和IL-8的合成和分泌，并激活表达 癌基因，C-MYC和PI3K/AKT信号通路，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，血管生成增加以及产生 增长促进癌基产品。体外卵巢肿瘤细胞中PTTG表达的下调 它在动物中的缺失（淘汰）导致肿瘤发育的减少，这表明其重要 在维持癌症表型中的作用。本应用程序的长期目标是了解 PTTG在卵巢肿瘤发生和验证PTTG中的作用是抗抗菌发展的分子靶标 肿瘤剂。在此应用中，我们建议：i）确定PTTG过表达的影响 裸鼠细胞转化和肿瘤发育的卵巢上皮细胞； ii）确定 PTTG在卵巢表面上皮细胞中的过表达对卵巢肿瘤起源的影响 和转基因动物的转移，并确定支持肿瘤生长和转移的机制； iii）确定卵巢肿瘤细胞中PTTG表达下调的影响 抑制和转移，并确定导致肿瘤生长抑制和的机制 转移。这些研究将提供有关卵巢中PTTG机制的关键信息 肿瘤发生和转移并为开发小分子抑制PTTG的基础 充当抗肿瘤剂。另外，从我们的研究开发的转基因动物模型可以 加强旨在开发卵巢癌检测，预防和治疗方法的新方法。