Novel effectors of ERK signaling and their potential roles in the treatment of en

ERK 信号传导的新型效应物及其在治疗 en 中的潜在作用

• 批准号: 7727351
• 负责人: Liang Ma
• 金额: $ 9.34万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-18 至 2012-08-12
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7727351
• 关键词: Accounting; Antibodies; Apoptosis; Biological Models; Biological Response Modifier Therapy; Caenorhabditis elegans; Cancer Biology; Cancer Cell Growth; Cancer Model; Cancer cell line; Cell Cycle Regulation; Cell Line; Cell Proliferation; Cell Survival; Cells; Clinical; Detection; Diagnostic; Disease; Endometrial; Endometrial Carcinoma; Endometrium; Event; FGFR2 gene; Hemorrhage; Human; Instruction; KRAS2 gene; Lead; Malignant Female Reproductive System Neoplasm; Malignant Neoplasms; Maps; Methods; Mitogen-Activated Protein Kinases; Mitogens; Modeling; Molecular Abnormality; Morbidity - disease rate; Mutation; Neoplasm Metastasis; Operative Surgical Procedures; Orthologous Gene; Pathway interactions; Patients; Pharmacotherapy; Phosphorylation; Phosphorylation Site; Phosphotransferases; Play; Population; Postmenopause; Prevention; Proteins; Recurrent Malignant Neoplasm; Reproduction spores; Reverse Transcriptase Polymerase Chain Reaction; Role; Signal Pathway; Signal Transduction; Signal Transduction Pathway; Small Interfering RNA; Staging; Systemic disease; Therapeutic; Therapeutic Intervention; Tissue Microarray; Tissues; Tumor Suppressor Genes; Uterine Cancer; Western Blotting; Work; angiogenesis; carcinogenesis; cell growth; cell motility; chemotherapy; clinically relevant; cohort; effective therapy; extracellular; functional genomics; glycogen synthase kinase 3 beta; improved; mortality; multimodality; neoplastic; novel; novel strategies; novel therapeutic intervention; small hairpin RNA; treatment strategy; tumorigenesis

Endometrial carinoma is the most common cancer of the female reproductive tract. Most endometrial cancers are found at an early stage and present with postmenopausal bleeding. These patients are initially treated with comprehensive surgical staging. This treatment is often diagnostic ofthe extent of disease and therapeutic. However, a key clinical problem in the management of patients with uterine cancers is how to best fre¿t~ab\r¿rhced'stagieclisease ahdlhe aggressive pathoTogic histotypes that account for signficant mortality. Patients with high stage or recurrent cancers have systemic disease requiring novel therapeutic interventions. Effective therapies are largely lacking. A better understanding ofthe cancer biology, such as signal transduction pathways, will lead to new treatment strategies that will improve the survival of these patients. Activation of the Mitogen Activating Pathway Kinase signaling pathway contributes substantially to endometrial tumorigenesis. Our group has identified thirty novel ERK substrates through a three-part functional genomic approach in the C. elegans model. The human orthologs of these proteins expressed in endometrial cancer cell lines are candidate ERK substrates. Thus far, of the candidates studied, we showed that GSK3n is important to cell growth in multiple endometrial cancer cell lines and has potential for therapeutic interventions.. In this proposal, we will continue to characterize novel ERK candidate substrates in endometrial cancer. In Aim 1, we will assess expression of candidate ERK1/2 substrates in the normal endometrium, primary endometrial cancers and endometrial cancer cell lines and determine if substrate phosphorylation is ERK-dependent. Then in aim 2, we will determine the relationship between ERK substrate phosphorylation status and upstream ERK signaling pathway activation in primary endometrial cancers and clinicopathologic significance of ERK substrate expression. Finally in aim 3, we will explore GSKSD inhibition as potential therapy for endometrial cancer and assess the role of inhibiting other ERK substrates plays in endometrial cancer cell lines. Together these studies should provide a better understanding of the role the ERK pathway plays in endometrial carcinogenesis and may lead to improved clinical biological therapies. RELEVANCE (See instructions): The work proposed will lead to both an improved understanding of endometrial cancer biology and new approaches to the detection, prevention and treatment of uterine cancers which will result in reduced cancer morbidity and mortality.

子宫内膜性颈瘤是女性生殖道的最常见癌症。最大的子宫内膜 癌症是在早期发现的，并在绝经后出血。这些患者最初是 通过全面的手术分期治疗。这种治疗通常是诊断疾病程度和 治疗性。但是，子宫癌患者管理中的关键临床问题是如何 最好的自由t〜ab \r¿ 死亡。 高阶段或经常性癌症患者患有全身性疾病，需要新的治疗 干预措施。有效的疗法在很大程度上缺乏。更好地了解癌症生物学，例如 信号转导途径将导致新的治疗策略，以改善这些策略 患者。有丝分裂激活途径激活途径激酶信号通路的激活极大地促进 子宫内膜肿瘤发生。我们的小组通过三部分确定了三十个新颖的ERK底物 秀丽隐杆线虫模型中的功能基因组方法。这些蛋白质的人类直系同源物在 子宫内膜癌细胞系是候选ERK底物。在研究候选人的那个远处，我们表明 GSK3N对于多种子宫内膜癌细胞系中的细胞生长很重要，并且有潜力 治疗性干预措施。在此提案中，我们将继续描述新型ERK候选底物 在子宫内膜癌中。在AIM 1中，我们将评估正常情况下候选ERK1/2底物的表达 子宫内膜，原发子宫内膜癌和子宫内膜癌细胞系，并确定底物是否 磷酸化是ERK依赖性的。然后在AIM 2中，我们将确定ERK基板之间的关系 原发子宫内膜癌和上游ERK信号通路的磷酸化状态和上游ERK信号通路激活 ERK底物表达的临床病理学意义。终于在AIM 3中，我们将探索GSKSD 抑制作为子宫内膜癌的潜在疗法和评估抑制其他ERK底物的作用 在子宫内膜癌细胞系中发挥作用。这些研究在一起应该更好地理解 角色ERK途径在子宫内膜致癌中发挥作用，并可能导致临床生物学改善 疗法。 相关性（请参阅说明）： 提出的工作将导致对子宫内膜癌生物学和新的新了解 检测，预防和治疗子宫癌的方法，这将导致癌症减少 发病率和死亡率。