Role of TGFbeta signaling in HNSCC progression

TGFbeta 信号传导在 HNSCC 进展中的作用

• 批准号: 7886223
• 负责人: Xiao-Jing Wang
• 金额: $ 39.47万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-03-01 至 2015-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7886223
• 关键词: 4-Hydroxy-Tamoxifen; Abbreviations; Alcohols; Anthracenes; Arts; Benign; Binding; Biological Markers; Biology; Cancer Prognosis; Cells; Chronic; Collagen; Country; Data; Defect; Development; Down-Regulation; Elements; Environmental Carcinogens; Epithelial; Epithelial Cells; Epithelium; Event; Experimental Models; Family member; Fanconi' s Anemia; Fibroblasts; Funding; Gene Targeting; Genes; Genetically Engineered Mouse; Genomic Instability; Goals; HRAS gene; Head and Neck Cancer; Head and Neck Squamous Cell Carcinoma; Head and neck structure; Human; Immunohistochemistry; Inflammation; Lead; Loss of Heterozygosity; Malignant Conversion; Malignant Neoplasms; Matrix Metalloproteinases; Mediating; Mesenchymal; Microarray Analysis; Molecular; Molecular Target; Mouth Neoplasms; Mus; Mutation; Oncogenic; Pathway Analysis; Pathway interactions; Patients; Play; Poly(ADP-ribose) Polymerases; Production; Role; Signal Pathway; Signal Transduction; Squamous cell carcinoma; System; Testing; Therapeutic; Tissues; Tobacco; Transforming Growth Factor beta; Transforming Growth Factors; Up-Regulation; Vascular Endothelial Growth Factors; angiogenesis; base; cancer type; carcinogenesis; chemical carcinogen; chromatin immunoprecipitation; comparative genomic hybridization; cytokine; dimethylbenzanthracene; genome wide association study; genome-wide; improved; laser capture microdissection; macrophage stimulating protein; member; mouse model; novel therapeutic intervention; oral fibroblast; oral tissue; outcome forecast; overexpression; paracrine; promoter; public health relevance; receptor; tumor

DESCRIPTION (provided by applicant): The long term goal is to identify molecular targets that can be used for prognosis and therapy of HNSCC. Head & neck squamous cell carcinomas (HNSCC) represent the 6th most common cancer type in western countries. The major HNSCC etiological factors are environmental carcinogens, e.g., tobacco and alcohol, which cause genetic alterations and chronic inflammation in head & neck (H&N) tissues. In this application, we will use an inducible H&N-specific gene targeting system to introduce several genetic alterations in the TGF¿ signaling pathway, which are common in human HNSCC, into mouse H&N tissues, and assess the mechanisms by which these alterations promote HNSCC development. Aim 1 will examine molecular mechanisms of Smad4 loss-mediated HNSCC development. We will assess if any Fanc/Brca members are direct Smad4 transcriptional targets, and if VEGF overexpression in Smad4-/- HNSCCs is the result of Smad3 activation and contributes to Smad4 loss-mediated HNSCC carcinogenesis. Genome-wide analyses will be performed to identify additional alterations caused by Smad4 loss, which contribute to oncogenic effects on H&N epithelia and stroma. Aim 2 will assess the role of Smad2 loss in HNSCC promotion. We will determine if Smad2 loss promotes HNSCC formation and progression in the presence of a Kras mutation. We will analyze if increased HGF signaling found in Smad2-/- tissues contributes to Smad2 loss-associated oncogenic effects and study the mechanisms of HGF upregulation in Smad2-/- cells. Genome-wide screens will also be performed to identify molecular alterations caused by Smad2 loss in H&N tissues. Aim 3 will assess the role of stromal TGF¿RII loss in HNSCC development. We will induce TGF¿RII deletion in oral fibroblasts to ascertain if this will induce or promote HNSCC formation in the presence of either a chemical carcinogen-induced H-ras mutation or TGF¿RII deletion in H&N epithelia. Pathological and molecular alterations caused by oral fibroblast TGF¿RII deletion will be analyzed. These studies will not only improve our understanding of HNSCC biology, but will also directly test therapeutic approaches in HSNCC with specific TGF¿ signaling defects. PUBLIC HEALTH RELEVANCE: The application will use state-of-the-art experimental models and approaches to identify molecular mechanisms that cause head & neck cancer formation and progression. The proposed studies will lead to the identification of biomarkers that can be used to improve cancer prognosis and therapy.

描述（由适用提供）：长期目标是确定可用于HNSCC预后和治疗的分子靶标。头部和颈部鳞状细胞癌（HNSCC）代表了西方国家中第六种最常见的癌症类型。 HNSCC的主要病因因素是环境致癌物，例如烟草和酒精，它会导致遗传改变和头颈（H＆N）组织的慢性注射。在此应用中，我们将使用诱导的H＆N特异性基因靶向系统在人体HNSCC中常见的TGF信号途径中引入几种遗传改变，并评估这些改变促进HNSCC发育的机制。 AIM 1将检查SMAD4损耗介导的HNSCC发展的分子机制。我们将评估任何FANC/BRCA成员是否是直接的SMAD4转录靶标，并且是否在SMAD4 - / - HNSCC中的VEGF过表达是SMAD3激活的结果，并有助于SMAD4损失介导的HNSCC癌变。将进行全基因组分析，以确定由SMAD4损失引起的其他改变，这有助于对H＆N上皮菌和基质的致癌作用。 AIM 2将评估SMAD2损失在HNSCC促销中的作用。我们将确定在存在KRAS突变的情况下，SMAD2损失是否促进了HNSCC的形成和进展。我们将分析SMAD2 - / - 组织中发现的HGF信号的增加是否有助于SMAD2损失相关的致癌作用，并研究SMAD2 - / - 细胞中HGF上调的机制。还将进行全基因组筛查，以鉴定由H＆N组织中SMAD2损失引起的分子改变。 AIM 3将评估基质TGF¿RII损失在HNSCC开发中的作用。我们将在口服成纤维细胞中诱导tgf¿RII缺失，以确定在H＆n上皮素中具有化学致癌物诱导的H-RAS突变或TGF¿RII缺失的情况下，这是否会诱导或促进HNSCC形成。将分析由口服成纤维细胞TGF¿RII缺失引起的病理和分子改变。这些研究不仅会提高我们对HNSCC生物学的理解，而且还将直接通过特定TGF信号缺陷来直接测试HSNCC中的治疗方法。 公共卫生相关性：该应用将使用最先进的实验模型和方法来识别导致头颈癌形成和进展的分子机制。拟议的研究将导致鉴定可用于改善癌症疾病和治疗的生物标志物。