CD44-p185HER2 Interaction in Ovarian Cancer Progression

CD44-p185HER2 在卵巢癌进展中的相互作用

• 批准号: 7176180
• 负责人: Lilly YW Bourguignon
• 金额: $ 37.09万
• 依托单位: NORTHERN CALIFORNIA INSTITUTE/RES/EDU
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-04-01 至 2011-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7176180
• 关键词: Abnormal Cell; Ankyrins; Behavior; Binding; Biochemical; Biological; CD44 gene; Cancer Patient; Catalytic RNA; Cell Survival; Complex; Cytoskeleton; Development; Dominant-Negative Mutation; Drug Delivery Systems; ERBB2 gene; Early Diagnosis; Epithelial Cells; Evaluation; Event; Figs - dietary; Growth; Human; Immunohistochemistry; Malignant - descriptor; Malignant neoplasm of ovary; Mediating; Membrane; Messenger RNA; Molecular; Neoplasm Metastasis; Numbers; Oncogenic; Ovarian; Ovarian Carcinoma; Pathway interactions; Patients; Phenotype; Phosphotransferases; Procedures; Production; Property; Protein Isoforms; Proto-Oncogene Proteins c-akt; Research Proposals; SRC gene; Screening for Ovarian Cancer; Signal Pathway; Signal Transduction; Signaling Molecule; Site; Staining method; Stains; Structure; Techniques; Testing; Therapeutic; Tissues; Tumor Cell Invasion; Tumor Markers; base; cell behavior; cell growth; design; gene therapy; human EMS1 protein; inhibitor/antagonist; migration; mutant; neoplastic cell; novel; outcome forecast; ovarian neoplasm; polypeptide; protein-tyrosine kinase c-src; research study; src-Family Kinases; tumor; tumor progression

DESCRIPTION (provided by applicant): Both CD44 and p185HER2 confer the malignant properties of abnormal cell growth, migration and invasion. Furthermore, CD44 forms a complex with p185HER2 and these two molecules closely interact with a number of signaling molecules, thereby activating cytoskeleton function and tumor-specific phenotypes. In this continuation research proposal, we plan to test the hypothesis that CD44-p185HER2 interaction with specific signaling molecules (e g Vav2, Grb2, c-Src kinase and AKT) promotes the concomitant activation of multiple signaling pathways leading to cytoskeleten changes, tumor cell-specific behaviors (e.g. tumor cell growth, survival, invasion and migration) and ovarian cancer progression. To test this hypothesis, we plan to use a variety of biochemical, molecular biological techniques and immunohistochemical staining to elucidate CD44-p185HER2 interaction with the various signaling molecules. We will evaluate the functional ramifications of these interactions with respect to cytoskeleton changes and tumor cell-specific behaviors (e.g. tumor cell growth, survival, migration and invasion). In addition, we plan to analyze the co-expression of CD44v-p185HER2 and various signaling molecules (e.g. Vav2, c-Src and/or AKT) in human ovarian carcinoma tissues obtained from ovarian cancer patients using immunohistochemistry. We will also employ a novel signaling perturbation strategy to impair CD44-p185HER2 interaction with Racl/Ras signaling and c- Src/AKT activation by constructing a number of Vav2/Grb2 and c-Src/AKT dominant negative mutants Finally, we will establish a therapeutic antisense and ribozyme gene therapy procedures to specifically inhibit the mRNA encoding selected CD44 isoforms (and/or p185HER2) in order to effectively block the expression of these CD44 isoforms (and/or p185HER2) involved in Racl/Ras signaling, c-Src/AKT activation and the downstream oncogenic signaling events (e g cytoskeleton changes, tumor cell growth, survival, migration and invasion) These studies may identify useful structure/function-related markers for ovarian cancer detection and prognosis. We believe that the new information obtained from this proposal may establish the CD44-p185HER2 complex and associated signaling molecules as important tumor markers for the early detection and evaluation of oncogenic potential, as well as allow the development of new drug targets to inhibit CD44-p185HER2-mediated ovarian cancer progression.

描述（由申请方提供）：CD 44和p185 HER 2均赋予异常细胞生长、迁移和侵袭的恶性特性。此外，CD 44与p185 HER 2形成复合物，这两种分子与许多信号分子密切相互作用，从而激活细胞骨架功能和肿瘤特异性表型。在这项继续研究计划中，我们计划检验以下假设：CD 44-p185 HER 2与特定信号分子（例如Vav 2、Grb 2、c-Src激酶和AKT）的相互作用促进多种信号通路的同时激活，导致细胞骨架变化、肿瘤细胞特异性行为（例如肿瘤细胞生长、存活、侵袭和迁移）和卵巢癌进展。为了验证这一假设，我们计划使用各种生物化学，分子生物学技术和免疫组化染色来阐明CD 44-p185 HER 2与各种信号分子的相互作用。我们将评估这些相互作用对细胞骨架变化和肿瘤细胞特异性行为（例如肿瘤细胞生长、存活、迁移和侵袭）的功能影响。此外，我们计划使用免疫组织化学分析从卵巢癌患者获得的人卵巢癌组织中CD 44 v-p185 HER 2和各种信号分子（例如Vav 2、c-Src和/或AKT）的共表达。我们还将采用一种新的信号干扰策略，通过构建许多Vav 2/Grb 2和c-Src/AKT显性负突变体来削弱CD 44-p185 HER 2与Rac 1/Ras信号和c-Src/AKT活化的相互作用。我们将建立一种治疗性的反义和核酶基因治疗程序，以特异性地抑制编码选定的CD 44亚型的mRNA（和/或p185 HER 2）以有效地阻断这些CD 44同种型的表达（和/或p185 HER 2）参与Racl/Ras信号传导、c-Src/AKT活化和下游致癌信号传导事件（例如细胞骨架变化，肿瘤细胞生长，存活，这些研究可以鉴定用于卵巢癌检测和预后的有用的结构/功能相关标志物。我们相信，从这一提议中获得的新信息可能会建立CD 44-p185 HER 2复合物和相关信号分子作为重要的肿瘤标志物，用于早期检测和评估致癌潜力，以及允许开发新的药物靶点来抑制CD 44-p185 HER 2介导的卵巢癌进展。