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（终身教授），主要临床兴趣是内分泌外科肿瘤学和基础科学研究培训。她非常致力于将自己打造成甲状腺癌研究领域的独立研究者的长期职业目标。她一直在一个非常协作和协同的环境中工作，机构对她的学术成功做出了重大承诺。她正在申请该奖项，目的是最终能够申请 NIH R01 资助并建立自己的研究项目。她对该奖励机制的职业发展计划包括正式课程作业以及参加与其研究领域相关的研讨会和会议，目的是增加癌症基因调控机制的教学和实践知识。此外，她将与导师和研究审查委员会密切互动，以确保她走向独立。甲状腺癌是影响内分泌腺的最常见恶性肿瘤，其发病率在过去 30 年中一直在上升。它不是一种普遍致命的恶性肿瘤。然而，据报道，复发性疾病（发生在 25% 的患者中）会增加随后的死亡率，甚至是分化良好的甲状腺癌。分化良好的肿瘤通常通过手术和放射性碘消融来治疗。然而，复发通常对放射性碘的反应较差，并且不可能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（例如未分化肿瘤）具有很强的侵袭性，目前尚无有效的治疗方法。初步研究表明，细胞外基质1（ECM1）在未分化甲状腺癌中过度表达，其表达可能是分化型甲状腺恶性肿瘤的预后指标。使用细胞系模型进行的其他初步研究表明 TFAP2C 可能调节 ECM1 表达。这项工作的假设是，ECM1 是甲状腺癌的重要预后标志物，可增加转移潜力，并且其表达受 TFAP2 调节。本申请旨在扩大我们对 ECM1 过度表达的调节及其在预后中的作用的理解，其具体目标如下。 1) 确定ECM1转录调控机制，特别是TFAP2C； 2) 检查 ECM1 过表达和沉默对肿瘤细胞侵袭和转移潜力的作用，3) 检查 ECM1 表达作为甲状腺癌患者预后决定因素的作用，并确定它是否与 TFAP2C 共表达。荧光素酶测定将用于定义 ECM1 的启动子区域，染色质免疫沉淀将用于确定 TFAP2C 是否结合该区域。将使用体外侵袭和迁移测定以及原位小鼠模型中的体内评估 ECM1 过表达的影响。最后，将通过实时 RT-PCR 和免疫组织化学在医院甲状腺癌患者队列中检查 ECM1 表达，以确定其是否与临床结果相关。这项研究工作的意义和与健康的相关性在于，它将增加我们对甲状腺癌侵袭性和预后不良表型的分子和遗传基础的理解。这有望带来有关其发展的新见解，并增强我们为这些肿瘤和其他低风险肿瘤发现新颖和定向疗法的能力。