CD44-p185HER2 Interaction in Ovarian Cancer Progression

描述（由申请人提供）：CD44和p185HER2都赋予异常细胞生长、迁移和侵袭的恶性特性。此外，CD44与p185HER2形成复合物，这两个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。在这一后续研究计划中，我们计划验证CD44-p185HER2与特定信号分子（如Vav2、Grb2、c-Src激酶和AKT）的相互作用是否能促进多种信号通路的同时激活，从而导致细胞骨架变化、肿瘤细胞特异性行为（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化、分子生物学技术和免疫组织化学染色来阐明CD44-p185HER2与各种信号分子的相互作用。我们将评估这些相互作用在细胞骨架变化和肿瘤细胞特异性行为（如肿瘤细胞生长、存活、迁移和侵袭）方面的功能分支。此外，我们计划利用免疫组织化学方法分析CD44v-p185HER2和各种信号分子（如Vav2、c-Src和/或AKT）在卵巢癌患者卵巢癌组织中的共表达情况。我们还将采用一种新的信号扰动策略，通过构建一些Vav2/Grb2和c-Src/AKT显性负突变体，来破坏CD44-p185HER2与Racl/Ras信号的相互作用和c-Src/AKT的激活。我们将建立一种治疗性反义和核酶基因治疗程序，特异性抑制编码选定的CD44亚型（和/或p185HER2）的mRNA，以有效阻断这些CD44亚型（和/或p185HER2）的表达，这些CD44亚型（和/或p185HER2）参与Racl/Ras信号传导、c-Src/AKT激活和下游致癌信号传导事件(如细胞骨架变化、肿瘤细胞生长、存活、这些研究可能为卵巢癌的检测和预后提供有用的结构/功能相关标志物。我们相信，从本研究中获得的新信息可能会使CD44-p185HER2复合物和相关信号分子成为早期发现和评估致癌潜力的重要肿瘤标志物，并允许开发新的药物靶点来抑制CD44-p185HER2介导的卵巢癌进展。

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.