Lysophosphatidic Acid Signaling in Ovarian Cancer

卵巢癌中的溶血磷脂酸信号传导

• 批准号: 6890335
• 负责人: FANG-TSYR LIN
• 金额: $ 25.81万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-05-01 至 2007-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6890335
• 关键词: apoptosis; biological signal transduction; cell growth regulation; cell line; cell migration; cell proliferation; cell surface receptors; flow cytometry; fluorescence microscopy; gene expression; genetic regulation; genetic transcription; immunoprecipitation; lysophospholipids; microarray technology; neoplasm /cancer invasiveness; neoplastic process; ovary neoplasms; protein protein interaction; protein structure function; receptor expression; site directed mutagenesis; yeast two hybrid system

DESCRIPTION (provided by applicant): The overall goal of this proposal is to study the regulation of signaling pathways mediated by lysophosphatidic acid (LPA) and its associated receptors in ovarian cancer cells. LPA acid and its associated receptors, EDG2, EDG4 and EDG7 of the endothelial differentiation gene (EDG) family, have been shown to contribute to ovarian cancer cell proliferation and tumor invasion. Overexpression of EDG4 has been implicated in the progression of ovarian cancer. Thus, these LPA receptors could serve as therapeutic targets in ovarian cancer. In this proposal, we provided the first evidence for the regulation of EDG4 functions by the proapoptotic protein, Siva-1, and the focal adhesion molecule, TRIP6 (Thyroid Receptor Interacting Protein 6). Our long-term goal is to design nove strategies specifically targeting LPA receptors for therapeutic treatment. Three specific aims will be addressed. In Aim 1, a role for Siva-1 in down-regulation of LPA signaling and induction of apoptosis will be determined. Biochemical approaches and yeast genetics wiIl be utilized to determine the functional significance of the interaction between Siva-1 and EDG4. In Aim 2, the role of TRIP6 in LPA-dependent, EDG4-mediated cell migration and mitogenic signaling will be explored by biochemical approaches and immunofluorescence microscopy. In Aim 3, the specificity of Siva-1 and TRIP6 in regulating different LPA receptors will be determined by biochemical approaches. The knowledge obtained from this study will gain insight into the understanding of LPA signaling and regulation in ovarian cancer.

描述（由申请人提供）：本提案的总体目标是研究溶血磷脂酸（LPA）及其相关受体在卵巢癌细胞中介导的信号通路调控。内皮分化基因（endothelial differentiation gene， EDG）家族的LPA酸及其相关受体EDG2、EDG4和EDG7已被证明参与卵巢癌细胞增殖和肿瘤侵袭。EDG4的过表达与卵巢癌的进展有关。因此，这些LPA受体可作为卵巢癌的治疗靶点。在这项研究中，我们首次提供了凋亡前蛋白Siva-1和局灶黏附分子TRIP6（甲状腺受体相互作用蛋白6）调控EDG4功能的证据。我们的长期目标是设计专门针对LPA受体的治疗策略。将讨论三个具体目标。在Aim 1中，将确定Siva-1在下调LPA信号和诱导凋亡中的作用。生化方法和酵母遗传学将被用来确定Siva-1和EDG4相互作用的功能意义。在Aim 2中，将通过生化方法和免疫荧光显微镜探索TRIP6在lpa依赖、edg4介导的细胞迁移和有丝分裂信号传导中的作用。在Aim 3中，Siva-1和TRIP6调节不同LPA受体的特异性将通过生化方法确定。从本研究中获得的知识将有助于了解LPA信号传导和调控在卵巢癌中的作用。