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: 7998178
• 负责人: Sham S. Kakar
• 金额: $ 24.55万
• 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 2012-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7998178
• 关键词: 5q35.1; Address; Adenoviruses; Aneuploidy; Animal Model; Antineoplastic Agents; Base Sequence; Boxing; Cancer Model; Cause of Death; Cell Proliferation; Cell Survival; Cells; Cessation of life; Chromosomal Instability; Chromosome abnormality; Chromosomes; Complementary DNA; Crossbreeding; Cytoplasm; Data; Detection; Developed Countries; Development; Down-Regulation; Endometrium; 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 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; Signal Pathway; Sister Chromatid; Sister Chromatid Exchange; Small Interfering RNA; Staging; Structure; Surface; System; Testicular Neoplasms; 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.

卵巢癌是女性第五大最常诊断的癌症，也是导致卵巢癌的最常见原因。 美国死于妇科恶性肿瘤的人数。启动和支持的分子机制 卵巢肿瘤的发生尚不明确。我们克隆了一种新的致癌基因“PTTG”，也称为 securin 人类睾丸和卵巢肿瘤并研究其在肿瘤发生中的功能。 PTTG是一种多功能蛋白质 在许多肿瘤中高表达，包括卵巢肿瘤。将PTTG引入NIH3T3并 HEK293细胞在裸鼠体内诱导细胞转化并促进肿瘤形成，表明其 强致癌功能。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 增加 bFGF、VEGF 和 IL-8 的合成和分泌，并激活 癌基因、c-myc 和 PI3K/AKT 信号通路，表明 PTTG 的致癌活性可能 涉及非整倍体和染色体不稳定的诱导、血管生成的增加以及 促进生长的癌基因产品。体外卵巢肿瘤细胞PTTG表达下调 在动物中删除它（敲除）会导致肿瘤发展减少，这表明它的重要性 维持癌症表型的作用。该应用程序的长期目标是了解 PTTG 在卵巢肿瘤发生中的作用并验证 PTTG 作为开发抗卵巢肿瘤的分子靶点 肿瘤剂。在此应用中，我们建议：i) 确定 PTTG 过表达的影响 卵巢上皮细胞对裸鼠细胞转化和肿瘤发生的影响； ii) 确定 卵巢表面上皮细胞PTTG过表达对卵巢肿瘤发生、进展的影响 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表达下调对肿瘤的影响 抑制和转移并确定导致抑制肿瘤生长和的机制 转移。这些研究将提供有关卵巢 PTTG 机制的重要信息 肿瘤的发生和转移，为开发抑制PTTG的小分子奠定基础 作为抗肿瘤剂。此外，我们的研究开发的转基因动物模型可以 加强努力开发检测、预防和治疗卵巢癌的新方法。

项目成果

Tumorigenic potential of pituitary tumor transforming gene (PTTG) in vivo investigated using a transgenic mouse model, and effects of cross breeding with p53 (+/-) transgenic mice.

• DOI: 10.1186/1471-2407-12-532
• 发表时间: 2012-11-20
• 期刊: BMC cancer
• 影响因子: 3.8
• 作者: Fong MY;Farghaly H;Kakar SS
• 通讯作者: Kakar SS

Synergistic cytotoxic action of cisplatin and withaferin A on ovarian cancer cell lines.

• DOI: 10.1016/j.bbrc.2012.06.047
• 发表时间: 2012-07-13
• 期刊: BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
• 影响因子: 3.1
• 作者: Kakar, Sham S.;Jala, Venkatakrishna R.;Fong, Miranda Y.
• 通讯作者: Fong, Miranda Y.

Pituitary tumor transforming gene induces epithelial to mesenchymal transition by regulation of Twist, Snail, Slug, and E-cadherin.

• DOI: 10.1016/j.canlet.2011.06.033
• 发表时间: 2011-12-01
• 期刊: CANCER LETTERS
• 影响因子: 9.7
• 作者: Shah, Parag P.;Kakar, Sham S.
• 通讯作者: Kakar, Sham S.

Identification of metabolites in the normal ovary and their transformation in primary and metastatic ovarian cancer.

鉴定正常卵巢中的代谢产物及其在原发性和转移性卵巢癌中的转化。

• DOI: 10.1371/journal.pone.0019963
• 发表时间: 2011
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Fong MY;McDunn J;Kakar SS
• 通讯作者: Kakar SS

Withaferin A (WFA) inhibits tumor growth and metastasis by targeting ovarian cancer stem cells.

• DOI: 10.18632/oncotarget.20170
• 发表时间: 2017-09-26
• 期刊: Oncotarget
• 作者: Kakar SS;Parte S;Carter K;Joshua IG;Worth C;Rameshwar P;Ratajczak MZ
• 通讯作者: Ratajczak MZ