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

描述（由申请人提供）：候选人是一名助理教授（终身制），主要临床兴趣是内分泌外科肿瘤学和基础科学研究培训。她非常致力于建立自己作为甲状腺癌研究领域的独立调查员的长期职业目标。她一直在一个非常协作和协同的环境中工作，并对她的学术成功做出了大量的机构承诺。她正在申请这个奖项，目的是最终能够申请NIH R 01拨款，并建立自己的研究计划。她的职业发展计划，这个奖励机制包括正式的课程工作和出席研讨会和会议有关她的研究领域的目标，以增加在癌症基因调控机制的教学和实践知识。此外，她将与她的导师和研究审查委员会密切互动，以确保她的进步，以独立。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。它并不是一种致命的恶性肿瘤。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，即使是分化良好的甲状腺癌。分化良好的肿瘤通常用手术和放射性碘消融治疗。然而，复发通常对放射性碘的反应较低，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，如间变性肿瘤是非常积极的，目前没有有效的治疗。初步研究表明，细胞外基质1（ECM 1）在甲状腺未分化癌中过度表达，其表达可能是分化型甲状腺恶性肿瘤的预后指标。使用细胞系模型的其他初步研究表明，TFAP 2C可能调节ECM 1表达。这项工作的假设是，ECM 1是甲状腺癌中一个重要的预后标志物，它赋予了增加的转移潜力，并且其表达受TFAP 2的调节。本申请旨在扩大我们对ECM 1过表达的调控及其在预后中的作用的理解，具体目标如下。1)确定ECM 1的转录调节机制，特别是TFAP 2C; 2）检查ECM 1过表达和沉默对肿瘤细胞侵袭和转移潜力的作用; 3）检查ECM 1表达作为甲状腺癌患者结局决定因素的作用，并确定其是否与TFAP 2C共表达。荧光素酶测定将用于确定ECM 1的启动子区域，染色质免疫沉淀将用于确定TFAP 2C是否结合该区域。将使用体外侵袭和迁移试验以及原位小鼠模型中的体内试验评价ECM 1过表达的影响。最后，将通过实时RT-PCR和免疫组织化学在甲状腺癌患者的医院队列中检查ECM 1表达，以确定其是否与临床结局相关。这项研究奋进的意义和健康相关性在于，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。这将有望导致关于它们的发展的新见解，并提高我们为这些和其他低风险肿瘤发现新的和定向疗法的能力。

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.