PTTG Role in Ovarian Tumorigenesis and Matastasis

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，也是妇科恶性肿瘤中最常见的死亡原因。启动和支持卵巢肿瘤发生的分子机制尚不明确。我们从人类睾丸和卵巢肿瘤中克隆了一种新的致癌基因PTTG，也被称为securin，并研究了它在肿瘤发生中的功能。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。PTTG导入NIH3T3和HEK293细胞后，在裸鼠体内诱导细胞转化，促进肿瘤形成，提示PTTG具有较强的致瘤功能。值得注意的是，PTTG已被证明可以抑制姐妹染色单体的分离，增加bFGF、VEGF和IL-8的合成和分泌，并激活癌基因、c-myc和PI3K/AKT信号通路的表达，这表明PTTG的致癌活性可能涉及诱导非整倍体和染色体不稳定性，增加血管生成，以及产生促进生长的癌基因产物。PTTG在卵巢肿瘤细胞中的体外表达下调及在动物体内的缺失（敲除）可减少肿瘤的发展，提示其在维持癌症表型中发挥重要作用。这项应用的长期目标是了解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。在这项应用中，我们提出：i)确定PTTG在卵巢上皮细胞中过表达对裸鼠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过表达对转基因动物卵巢肿瘤发生、发展和转移的影响，并确定支持肿瘤生长和转移的机制；iii)确定下调卵巢肿瘤细胞PTTG表达对肿瘤抑制和转移的影响，确定抑制肿瘤生长和转移的机制。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，从我们的研究中建立的转基因动物模型可以促进旨在开发卵巢癌检测，预防和治疗新方法的努力。

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.