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.

卵巢癌是女性中第五大最常见的癌症，也是女性中最常见的癌症。 在美国死于妇科恶性肿瘤。启动和支持 卵巢肿瘤的发生还没有很好的定义。我们克隆了一个新的癌基因“PTTG”，也被称为securin， 人类睾丸和卵巢肿瘤并研究其在肿瘤发生中的作用。PTTG是一种多功能蛋白质 并且在包括卵巢肿瘤在内的许多肿瘤中高度表达。将PTTG导入NIH 3 T3中， HEK 293细胞在裸鼠体内诱导细胞转化并促进肿瘤形成，提示其具有抗肿瘤作用。 强致癌功能。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，并激活 癌基因、c-myc和PI 3 K/AKT信号通路，提示PTTG的致癌活性可能与PTTG的致癌活性有关。 包括诱导非整倍性和染色体不稳定性、增加血管生成和产生 促生长癌基因产物。卵巢肿瘤细胞PTTG表达下调的体外研究 在动物中其缺失（敲除）导致肿瘤发展减少，表明其重要性。 维持癌症表型的作用。本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作为开发抗肿瘤药物的分子靶点。 肿瘤剂。在本申请中，我们提出：i）确定PTTG过表达在人乳腺癌中的作用， 卵巢上皮细胞对裸鼠中细胞转化和肿瘤发展的影响; ii）确定 卵巢上皮细胞PTTG过表达对卵巢肿瘤发生、发展的影响 和转移，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表达的下调对肿瘤生长的影响， 抑制和转移，并确定导致抑制肿瘤生长机制， 转移这些研究将为PTTG在卵巢癌中的作用机制提供重要信息。 为开发抑制PTTG的小分子药物奠定了基础 用作抗肿瘤剂。此外，我们的研究开发的转基因动物模型可以 加强努力，旨在开发新的方法来检测，预防和治疗卵巢癌。

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