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）：