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

CD44

• 批准号: 8597353
• 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/8597353
• 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 头颈鳞状细胞癌 (HNSCC) 患者的生存率<50%，其中约 90% 的癌症具有很强的侵袭性并迅速侵入周围组织。晚期 HNSCC 的晚期发现和治疗方案不足都会导致这种致命疾病的预后不良。因此，非常需要鉴定调节 HNSCC 发展、肿瘤进展和化疗反应的细胞和分子信号传导成分。越来越多的证据表明，HNSCC 细胞过度表达某种 CD44 同工型 [CD44v3-透明质酸 (HA) 受体]，并且 HA-CD44v3 相互作用可促进肿瘤细胞迁移和侵袭所需的肌动蛋白激活剂 (N-WASP) 介导的细胞骨架功能。干细胞标记 Nanog 最初被描述为参与 Stat-3 信号传导和胚胎干 (ES) 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 一起似乎赋予了 HNSCC 细胞的恶性特性。最近，微小RNA-21（miR-21）也被证明与HNSCC进展的发病机制密切相关。因此，本提案的主要目标是研究由 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 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 的相互作用促进细胞骨架激活和 Nanog-Stat-3 信号传导，从而导致 miR-21 的产生。这些信号相互作用共同导致肿瘤细胞特异性行为（例如肿瘤细胞生长、迁移/侵袭、存活和化疗耐药）和 HNSCC 进展。为了解决这一假设，我们计划实现以下三个具体目标： 目标 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 Nanog-Stat-3 信号传导、miR- 21 生产，以及使用 HNSCC 细胞培养物产生的下游致癌事件；目标 2：使用含有人类 HNSCC 细胞异种移植物的体内小鼠模型，研究 HA/CD44v3 与 Nanog/Stat-3 信号传导和 miR-21 产生/功能对 HNSCC 进展的相互作用；目标 3：分析人类 HNSCC 组织（原发肿瘤和淋巴结转移）中 CD44v3、Nanog 和关键致癌信号分子的共表达以及 miR-21 的产生。将采用多种互补技术来研究 HA/CD44v3 介导的 N-WASP 与 Nanog-Stat-3 途径和 miR-21 表达/功能的相互作用。特别是，该提案中描述的新信号传导扰动策略（使用 CD44/Nanog/Stat-3 RNAi 和特定的抗 miR-21 抑制剂）应揭示化疗与抑制 CD44、Nanog、Stat-3 和miR-21可以显着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）一起作为人类 HNSCC 进展的肿瘤标志物，以及作为潜在的诊断和预后辅助手段。显然，该拟议项目对于为患有 HNSCC 的退伍军人患者开发重要的新治疗方法具有重要的临床潜力，使得这项工作与 VA 患者护理任务高度相关。 公共卫生相关性： 项目叙述 近年来，头颈部鳞状细胞癌已被认为是退伍军人群体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 同工型-Nanog 相互作用和 miR-21 产生/功能在调节 HNSCC 行为（例如肿瘤细胞迁移、生长、存活和多药耐药性）中的潜在作用，应该会对这种知之甚少的疾病产生有价值的见解。因此，该项目对于治疗患有 HNSCC 的退伍军人患者具有潜在的重要临床实用性；因此，它与退伍军人管理局的患者护理任务高度相关。