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）： 头颈部鳞状细胞癌（HNSCC）的抽象患者的存活率<50％，其中约90％的癌症非常侵略性，并且迅速入侵周围的组织。晚期HNSCC的晚期检测和治疗方案不足都导致这种致命疾病的预后不良。因此，非常需要确定调节HNSCC发育，肿瘤进展以及对化学治疗的反应的细胞和分子信号传导成分。积累的证据表明，HNSCC细胞过表达特定的CD44同工型[CD44V3-A HYALURONAN（HA）受体]，并且HA-CD44V3相互作用促进了肌动蛋白激活剂（N-WASP）介导的肿瘤细胞迁移和入侵所需的细胞骨骼功能。最初将干细胞标记Nanog描述为涉及Stat-3信号传导和胚胎（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，MicroRNA-21（miR-21）也被证明与HNSCC进展的发病机理密切相关。因此，该提案的主要目标是研究HA/CD44V3介导的N-WASP激活的Nanog在调节STAT-3特异性转录活性和HNSCC进展所需的致癌miR-21表达/功能中起作用。 具体而言，我们假设HA介导的CD44V3与N-WASP的相互作用促进了细胞骨架激活和Nanog-STAT-3信号传导，从而导致miR-21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，生存和化学抗性）和HNSCC进展。为了解决这一假设，我们计划追求以下三个具体目标：目标1：阐明新鉴定的HA介导的CD44V3与细胞骨骼激活剂N-WASP及其在调节Nanog-STAT-3信号传导中的作用，并使用HNSCC Cell Crubters调节Nanog-STAT-3信号传导，miR-21的生产，MIR-21产生和下降的下降Oncentic Evental; AIM 2：使用含有人类HNSCC细胞的异种移植物的体内小鼠模型，研究HNSCC进程上HA/CD44V3与Nanog/Stat-3信号传导和MiR-21产生/功能的相互作用；和目标3：分析人类患者HNSCC组织（原发性肿瘤和淋巴结转移酶）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，本提案中描述的新的信号扰动策略（使用CD44/Nanog/Stat-3 RNAi和特定的抗MIR-21抑制剂）应表明，化学疗法与CD44，Nanog，Stat-3和miR-21的抑制结合在一起可以显着提高当前药物治疗的效率。此外，这些提出的研究将允许将共表达的CD44V3，Nanog和各种信号分子与miR-21（在HNSCC患者样本中）结合使用，作为人类HNSCC进展的肿瘤标志物，以及潜在的诊断和预后的艾滋病。显然，该提议的项目具有为HNSCC的资深患者开发重要的新治疗方法的重要临床潜力，这使得这项工作与VA患者护理任务高度相关。 公共卫生相关性： 近年来，HNSCC在退伍军人口中被认为是非常普遍的恶性肿瘤，其中包括烟草和酒精的使用。我们提出的项目解决了HA/CD44V3同工型相互作用的潜在作用，以及miR-21的产生/功能在调节HNSCC行为（例如肿瘤细胞迁移，生长，生存，生存和多药耐药性）中应产生对这种贫困理解疾病的有价值的见解。因此，该提出的项目具有潜在的重要临床实用性，用于治疗HNSCC的老将患者。因此，它与VA患者护理任务高度相关。