Regulation of Extracellular Matrix 1(ECM1) and its role in thyroid carcinogenesis

细胞外基质1(ECM1)的调控及其在甲状腺癌发生中的作用

• 批准号: 8898736
• 负责人: Geeta Lal
• 金额: $ 16.63万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-23 至 2016-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8898736
• 关键词: 1q21; Ablation; Accounting; Affect; Aggressive behavior; Area; Award; Basic Science; Binding; Biological Assay; Breast Epithelial Cells; Cancer Patient; Cancer Prognosis; Cancer cell line; Cell Line; Characteristics; Chromosome Mapping; Classification; Clinical; Complication; Development; Development Plans; Diagnosis; Diagnostic; Disease; Endocrine; Endocrine Glands; Ensure; Environment; External Beam Radiation Therapy; Extracellular Matrix; Gene Expression Regulation; Goals; Grant; Health; Hospitals; Human; Immunohistochemistry; In Vitro; Incidence; Iodine; Knowledge; Lead; Luciferases; Malignant Neoplasms; Malignant neoplasm of thyroid; Mammary Neoplasms; Mentors; Migration Assay; Modeling; Molecular; Molecular Genetics; Neoplasm Metastasis; Operative Surgical Procedures; Outcome; Patients; Phenotype; Prognostic Marker; Promoter Regions; Proteins; Radioactive Iodine; Radiosurgery; Recurrence; Recurrent disease; Regulation; Repeat Surgery; Reporting; Research; Research Personnel; Reverse Transcriptase Polymerase Chain Reaction; Review Committee; Risk; Role; Surgical Oncology; System; TFAP2A gene; TFAP2C gene; Thyroid Gland; Time; Training; Transcriptional Regulation; Undifferentiated; United States National Institutes of Health; Work; anaplastic thyroid cancer; angiogenesis; anticancer research; base; carcinogenesis; career; career development; chemotherapy; chromatin immunoprecipitation; cohort; conventional therapy; differential expression; effective therapy; genome wide association study; high risk; in vivo; insight; interest; migration; mortality; mouse model; neoplastic cell; novel; outcome forecast; overexpression; professor; programs; promoter; success; symposium; therapeutic target; therapy development; thyroid neoplasm; transcription factor; trend; tumor; tumor progression; young woman

DESCRIPTION (provided by applicant): The candidate is an Assistant Professor (tenure track) with primary clinical interest in Endocrine Surgical Oncology and training in basic science research. She is very committed to a long-term career goal of establishing herself as an independent investigator in the area of thyroid cancer research. She has been working in a very collaborative and synergistic environment with substantial institutional commitment to her academic success. She is applying for this award with the intent of eventually being able to apply for an NIH R01 grant and establish her own research program. Her career development plan for this award mechanism includes formal course work and attendance at seminars and conferences pertinent to her field of research with a goal to increase both didactic and practical knowledge in the mechanisms of gene regulation in cancers. In addition, she will interact closely with her mentors and Research Review Committee to ensure that she progresses to independence. Thyroid cancer is the most common malignancy affecting the endocrine glands and its incidence rates have been rising over the past 30 years. It is not a uniformly fatal malignancy. However, recurrent disease (occurring in 25% of patients) has been reported to increase subsequent mortality, even from well- differentiated thyroid cancers. Well-differentiated tumors are typically treated with surgery and radio-active iodine ablation. However, recurrences are often less responsive to radioactive iodine and it is not possible to reliably predict which tumors will recur or metastasize. In addition, some types of thyroid cancer such as anaplastic tumors are very aggressive and currently have no effective therapy. Preliminary studies suggest that Extracellular Matrix 1 (ECM1) is over-expressed in anaplastic thyroid cancers and that its expression may be a prognostic indicator in differentiated thyroid malignancies. Additional preliminary studies using cell line models indicate that TFAP2C likely regulates ECM1 expression. The hypothesis underlying the proposed work is that ECM1 is an important prognostic marker in thyroid cancer that confers increased metastatic potential and that its expression is regulated by TFAP2. This application proposes to expand our understanding of the regulation of ECM1 overexpression and its role in prognosis with the following specific aims. 1) Determine the mechanisms of transcriptional regulation of ECM1, with particular reference to TFAP2C; 2) Examine the role of ECM1 over-expression and silencing on invasive and metastatic potential of tumor cells and 3) Examine the role of ECM1 expression as a determinant of outcome in patients with thyroid cancer and determine whether it is co-expressed with TFAP2C. Luciferase assays will be used to define the promoter region of ECM1 and chromatin immunoprecipitation will be used to determine if TFAP2C binds this region. The effects of ECM1 overexpression will be evaluated using in vitro invasion and migration assays and in vivo in an orthotopic mouse model. Lastly, ECM1 expression will be examined by real-time RT-PCR and immunohistochemistry in a hospital-based cohort of patients with thyroid cancer to determine whether it correlates with clinical outcomes. The significance and health-relatedness of this research endeavor is that it will increase our understanding of the molecular and genetic basis of the aggressive and poor-prognosis phenotype of thyroid cancer. This will hopefully lead to new insights regarding their development and enhance our ability to discover novel and directed therapies for these and other poor-risk tumors.

描述（由申请人提供）：候选人是一名助理教授（任期），对内分泌手术肿瘤学和基础科学研究的培训具有主要临床兴趣。她非常致力于在甲状腺癌研究领域确立自己的独立研究者的长期职业目标。她一直在一个非常合作和协同的环境中工作，对她的学术成就有实质性的承诺。她正在申请该奖项，目的是最终能够申请NIH R01赠款并建立自己的研究计划。她的奖励机制的职业发展计划包括与她的研究领域有关的研讨会和会议的正式课程工作以及参加癌症基因调节机制的教学和实践知识的目标。此外，她将与导师和研究审查委员会紧密互动，以确保她发展到独立性。甲状腺癌是影响内分泌腺的最常见恶性肿瘤，在过去30年中，其发病率一直在上升。这不是统一的致命恶性肿瘤。但是，据报道，复发性疾病（发生在25％的患者中），即使是从良好分化的甲状腺癌中，也会增加随后的死亡率。分化良好的肿瘤通常通过手术和放射性碘消融治疗。但是，复发通常对放射性碘的反应较低，无法可靠地预测哪些肿瘤会复发或转移。此外，某些类型的甲状腺癌（例如型肿瘤）非常侵略性，目前尚无有效的治疗。初步研究表明，细胞外基质1（ECM1）在甲状腺甲状腺癌中过表达，其表达可能是分化甲状腺恶性肿瘤的预后指标。使用细胞系模型的其他初步研究表明，TFAP2C可能调节ECM1表达。拟议工作的基础假设是ECM1是甲状腺癌中重要的预后标记，它赋予了增加的转移潜力，并且其表达受TFAP2的调节。该应用程序建议通过以下特定目的扩展我们对ECM1过表达的调节及其在预后中的作用的理解。 1）确定ECM1转录调控的机制，特别是参考TFAP2C； 2）检查ECM1过表达和沉默对肿瘤细胞的侵入性和转移潜力的作用； 3）检查ECM1表达作为甲状腺癌患者的结果的作用，并确定其是否与TFAP2C共表达。荧光素酶测定将用于定义ECM1的启动子区域，并将使用染色质免疫沉淀来确定TFAP2C是否结合该区域。 ECM1过表达的效果将使用体外侵袭和迁移测定和原位小鼠模型中的体内进行评估。最后，将通过实时RT-PCR和免疫组织化学来检查ECM1的表达，甲状腺癌患者同类群体，以确定其是否与临床结果相关。这项研究努力的重要性和与健康相关性是，它将增加我们对甲状腺癌侵略性和预见表型的分子和遗传基础的理解。希望这将导致有关其发展的新见解，并增强我们为这些和其他贫困风险肿瘤发现新颖和定向疗法的能力。