CD44 & Stem Cell Marker (Nanog) in Head and Neck Cancer

CD44

• 批准号: 8196329
• 负责人: Lilly YW Bourguignon
• 金额: --
• 依托单位: VETERANS AFFAIRS MED CTR SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-10-01 至 2014-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8196329
• 关键词: Actins; Address; Alcohols; Animals; Behavior; Binding; CD44 Antigens; CD44 gene; Carcinoma; Cell Culture Techniques; Cell Line; Cell Surface Receptors; Cell Survival; Cell physiology; Cells; Chromosome Fragile Sites; Clinical; Cytoskeleton; Data; Detection; Development; Diagnostic; Disease; Effectiveness; Evaluation; Event; Exons; Extracellular Matrix; Gel; Genomics; Glycoproteins; Goals; Growth; Head and Neck Cancer; Head and Neck Squamous Cell Carcinoma; Human; Hyaluronan; In Situ Hybridization; In Vitro; Individual; Invaded; Knowledge; Lead; Ligands; Maintenance; Malignant - descriptor; Malignant Epithelial Cell; Malignant Neoplasms; Mediating; Membrane; Messenger RNA; MicroRNAs; Mission; Modeling; Molecular; Morbidity - disease rate; Multi-Drug Resistance; Mus; Neoplasm Metastasis; Nucleotides; Nude Mice; Oncogenic; Pathogenesis; Pathway interactions; Patient Care; Patients; Pharmaceutical Preparations; Phenotype; Physiological; Play; Population; Primary Neoplasm; Production; Property; Protein Isoforms; RNA Interference; RNA Splicing; Regulation; Research; Research Proposals; Resistance; Risk Factors; Role; Sampling; Signal Transduction; Signaling Molecule; Site; Small Interfering RNA; Small RNA; Staining method; Stains; Stem cells; Sublingual Region; Survival Rate; Techniques; Testing; Therapeutic; Tissues; Tobacco; Transcriptional Activation; Tumor Markers; Variant; Veterans; Work; Xenograft procedure; base; cell growth; cell motility; chemotherapeutic agent; chemotherapy; design; effective therapy; embryonic stem cell; extracellular; improved; in vivo; inhibitor/antagonist; insight; lymph nodes; migration; mortality; mouse model; neoplastic cell; novel marker; novel therapeutic intervention; outcome forecast; overexpression; pluripotency; prognostic; public health relevance; research study; response; self-renewal; transcription factor; treatment planning; tumor; tumor progression

DESCRIPTION (provided by applicant): ABSTRACT Patients with head and neck squamous cell carcinoma (HNSCC) have a survival rate of <50% with approximately 90% of these cancers being very aggressive and rapidly invading the surrounding tissues. Both late detection and inadequate treatment options for advanced HNSCC contribute to the poor prognosis of this deadly disease. Therefore, there is a great need to identify the cellular and molecular signaling components that regulate HNSCC development, tumor progression, and the response to chemotherapeutic treatment. Accumulating evidence indicates that HNSCC cells overexpress a certain CD44 isoform [CD44v3-a hyaluronan (HA) receptor] and that HA-CD44v3 interaction promotes actin activator (N-WASP)-mediated cytoskeleton functions required for tumor cell migration and invasion. The stem cell marker, Nanog, was initially described as an important transcription factor involved in Stat-3 signaling and embryonic stem (ES) cell functions. Our current results indicate that CD44v3, Nanog and Stat-3 together appear to confer the malignant properties of HNSCC cells. Recently, microRNA-21 (miR-21) is also shown to be closely associated with the pathogenesis of HNSCC progression. Therefore, the main goal of this proposal is to investigate whether Nanog, activated by HA/CD44v3-mediated N-WASP, plays a role in regulating Stat-3-specific transcriptional activities and oncogenic miR-21 expression/function required for HNSCC progression. Specifically, we hypothesize that the HA-mediated CD44v3 interaction with N-WASP promotes cytoskeleton activation and Nanog-Stat-3 signaling leading to miR-21 production. Together these signaling interactions result in tumor cell-specific behaviors (e.g., tumor cell growth, migration/invasion, survival and chemoresistance) and HNSCC progression. To address this hypothesis, we plan to pursue the following three specific aims: Aim 1: To elucidate the newly identified HA-mediated CD44v3 interaction with the cytoskeleton activator, N-WASP and its role in regulating Nanog-Stat-3 signaling, miR-21 production, and the resulting downstream oncogenic events using HNSCC cell cultures; Aim 2: To investigate HA/CD44v3 interaction with Nanog/Stat-3 signaling and miR-21 production/function on HNSCC progression using an in vivo mouse model containing xenografts of human HNSCC cells; and Aim 3: To analyze the co-expression of CD44v3, Nanog and key oncogenic signaling molecules along with miR-21 production in human patient HNSCC tissues (primary tumors and lymph node metastases). A variety of complementary techniques will be employed to investigate HA/CD44v3-mediated N-WASP interaction with the Nanog-Stat-3 pathway and miR-21 expression/functions. In particular, the new signaling perturbation strategies (using CD44/Nanog/Stat-3 RNAi, and a specific anti-miR-21 inhibitor) described in this proposal should reveal that chemotherapy combined with the suppression of CD44, Nanog, Stat-3 and miR-21 can significantly improve the efficacy of current drug treatments. Moreover, these proposed studies will allow the evaluation of co-expressed CD44v3, Nanog and various signaling molecules in conjunction with miR-21 (in HNSCC patient samples) as tumor markers for human HNSCC progression, and as potential diagnostic and prognostic aids. Clearly, this proposed project has important clinical potential for the development of important new treatment approaches for Veteran patients with HNSCC, making this work highly relevant to the VA patient care mission. PUBLIC HEALTH RELEVANCE: PROJECT NARRATIVE In recent years, HNSCC has been recognized as a very common malignancy in the Veteran population, with risk factors including tobacco and alcohol usage. Our proposed project addressing the potential role for HA/CD44v3 isoform-Nanog interactions and miR-21 production/function in regulating HNSCC behaviors (e.g., tumor cell migration, growth, survival and multidrug resistance) should yield valuable insights into this poorly understood disease. Thus, this proposed project has potentially important clinical utility for the treatment of Veteran patients with HNSCC; and therefore, it is highly relevant to the VA patient care mission.

描述(由申请人提供)： 摘要头颈部鳞状细胞癌(HNSCC)患者的存活率为50%，其中约90%是侵袭性很强且迅速侵犯周围组织的癌症。晚期HNSCC的晚期发现和治疗选择不足都是导致这种致命疾病预后较差的原因。因此，迫切需要确定调控HNSCC发展、肿瘤进展和化疗反应的细胞和分子信号成分。越来越多的证据表明，HNSCC细胞过度表达CD44亚型[CD44v3-a透明质酸(HA)受体]，HA-CD44v3相互作用促进肌动蛋白激活物(N-WASP)介导的细胞骨架功能，是肿瘤细胞迁移和侵袭所必需的。干细胞标记Nanog最初被描述为参与Stat-3信号转导和胚胎干细胞功能的重要转录因子。我们目前的结果表明，CD44v3、Nanog和Stat-3共同似乎与HNSCC细胞的恶性特性有关。最近，microRNA-21(miR-21)也被证明与HNSCC进展密切相关。因此，该方案的主要目的是研究由HA/CD44v3介导的N-WASP激活的Nanog是否在调节HNSCC进展所需的Stat-3特异性转录活性和致癌基因miR-21表达/功能中发挥作用。具体来说，我们假设HA介导的CD44v3与N-WASP的相互作用促进了细胞骨架的激活和Nanog-Stat-3信号导致miR-21的产生。这些信号相互作用共同导致肿瘤细胞的特异性行为(例如，肿瘤细胞的生长、迁移/侵袭、存活和化疗耐药)和HNSCC进展。为了解决这一假设，我们计划追求以下三个特定的目标：目的1：阐明新发现的HA介导的CD44v3与细胞骨架激活剂N-WASP的相互作用及其在调节HNSCC细胞培养的Nanog-Stat-3信号、miR-21产生以及由此产生的下游致癌事件中的作用；目的2：利用含人HNSCC细胞的体内模型，研究HA/CD44v3与Nanog/Stat-3信号和miR-21的相互作用在HNSCC进展中的作用；目的3：分析CD44v3、Nanog和关键致癌信号分子与miR-21在人HNSCC组织(原发肿瘤和淋巴结转移)中的共表达。将采用多种辅助技术来研究HA/CD44v3介导的N-WASP与Nanog-Stat-3途径的相互作用和miR-21的表达/功能。特别是，该建议中描述的新的信号干扰策略(使用CD44/Nanog/Stat-3 RNAi和特异性的抗miR-21抑制剂)应该揭示，化疗结合抑制CD44、Nanog、Stat-3和miR-21可以显著提高当前药物治疗的疗效。此外，这些拟议的研究将允许评估共表达的CD44v3、Nanog和各种信号分子与miR-21(在HNSCC患者样本中)作为人类HNSCC进展的肿瘤标记物，以及作为潜在的诊断和预后辅助手段。显然，这项拟议的项目对于为退伍军人HNSCC患者开发重要的新治疗方法具有重要的临床潜力，使这项工作与退伍军人管理局的患者护理任务高度相关。 公共卫生相关性： 项目简介近年来，HNSCC已被认为是退伍军人中非常常见的恶性肿瘤，其危险因素包括吸烟和饮酒。我们提出的项目旨在解决HA/CD44v3异构体-Nanog相互作用和miR-21生产/功能在调控HNSCC行为(例如，肿瘤细胞迁移、生长、生存和多药耐药)中的潜在作用，应该会对这种鲜为人知的疾病提供有价值的见解。因此，这个拟议的项目对治疗退伍军人HNSCC患者具有潜在的重要临床实用价值；因此，它与退伍军人管理局的患者护理任务高度相关。