Genetic and Epigenetic Alterations in Thyroid Tumors

甲状腺肿瘤的遗传和表观遗传改变

• 批准号: 7244434
• 负责人: MICHAEL Mingzhao XING
• 金额: $ 27.82万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-07-01 至 2011-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7244434
• 关键词: Acetylation; BRAF gene; Cancer Patient; Cell Line; Cells; Condition; DNA; DNA Methylation; DNA Methyltransferase; DNA Modification Methylases; DNA Sequence; DNA Sequence Rearrangement; Deacetylation; Development; Dominant-Negative Mutation; Endocrine; Epigenetic Process; Event; Failure; Frequencies; Gene Expression; Gene Silencing; Genes; Genetic; Genomics; Goals; Histone Deacetylation; Histones; Hormone Receptor; Human; Iodides; MAP Kinase Activation Pathway; MAP Kinase Signaling Pathways; MEKs; Malignant Neoplasms; Malignant neoplasm of thyroid; Messenger RNA; Metabolism; Methods; Methylation; Mitogen-Activated Protein Kinases; Modeling; Modification; Molecular; Morbidity - disease rate; Mutation; Numbers; Oncogene Proteins; Oncogenic; Papillary thyroid carcinoma; Pathogenesis; Pathway interactions; Pattern; Phosphotransferases; Play; Polymerase Chain Reaction; Principal Investigator; Process; Proteins; RNA; RNA Interference; Ras/Raf; Relative (related person); Reverse Transcriptase Polymerase Chain Reaction; Role; SLC5A5 gene; Small Interfering RNA; Techniques; Testing; Thyroid Gland; Thyroid carcinoma; Thyrotropin Receptor; Time; Title; Transfection; Tumor Suppressor Genes; Variant; Western Blotting; base; bisulfite; chromatin immunoprecipitation; concept; expression vector; human SLC5A5 protein; inhibitor/antagonist; kinase inhibitor; malignant endocrine gland neoplasm; mortality; mutant; neoplastic cell; novel therapeutics; programs; promoter; sodium-iodide symporter; therapeutic target; thyroid neoplasm; tumor; tumorigenesis

DESCRIPTION (provided by applicant): Papillary thyroid cancer (PTC), the most common endocrine malignancy, harbors several important oncogenic events, including BRAF mutation, Ras mutation, RET/PTC rearrangements, and methylation- induced silencing of the tumor suppressor gene RASSF1 A. Silencing of the thyroid-specific genes that are involved in iodide metabolism, such as the genes for thyroid-stimulating hormone receptor (TSHR) and sodium/iodide symporter (NIS), is responsible for the failure of some PTC patients to respond to radioiodine treatment. It is hypothesized that the oncogenic events, by activating the MAP kinase pathway, result in epigenetic alterations that are responsible for thyroid-specific gene silencing. To test this hypothesis, mutual exclusivity of the oncogenic events will first be tested in specific subtypes of PTC to support the concept that each oncogenic event is able to cause PTC through activating their shared MAP kinase pathway. Methylation status of thyroid-specific genes will be subsequently examined in the same tumors, with a focus on the TSHR and NIS genes, to define the relationship of oncogenic events with thyroid gene methylation. Human thyroid tumor cell lines with various oncogenic alterations, either naturally existing or experimentally created, will be used to study the functional relationship between the oncogenic events and thyroid gene methylation. Epigenetic histone modification and its relationship to DNA methylation in silencing thyroid genes and to oncogenic alterations will also be studied in cell lines. Specific kinase inhibitors and cell transfection with oncoproteins and siRNAs will be used to alter MAP kinase pathway activities in these studies. The role of BRAF mutation, the most common oncogenic event in PTC, and related MAP kinase pathway aberration in the epigenetic alteration and silencing of thyroid-specific genes will be the primary focus of these studies. We expect to discover important molecular information on the mechanisms of PTC pathogenesis and novel therapeutic targets for this most common endocrine cancer.

描述(申请人提供)：乳头状甲状腺癌(PTC)是最常见的内分泌恶性肿瘤，包含几个重要的致癌事件，包括BRAF突变、RAS突变、RET/PTC重排和肿瘤抑制基因RASSF1 A甲基化诱导的沉默。甲状腺特异基因的沉默涉及碘代谢，如促甲状腺激素受体(TSHR)和钠/碘同向转运体(NIS)基因，导致一些PTC患者对放射碘治疗无效。据推测，致癌事件通过激活MAP激酶途径，导致表观遗传学改变，从而导致甲状腺特异性基因沉默。为了验证这一假设，首先将在特定的PTC亚型中测试致癌事件的互斥性，以支持每个致癌事件能够通过激活其共享的MAP激酶途径而导致PTC的概念。随后将在相同的肿瘤中检查甲状腺特异基因的甲基化状态，重点是TSHR和NIS基因，以确定致癌事件与甲状腺基因甲基化的关系。具有各种致癌改变的人甲状腺肿瘤细胞系，无论是自然存在的还是实验建立的，都将被用来研究致癌事件和甲状腺基因甲基化之间的功能关系。表观遗传组蛋白修饰及其与DNA甲基化在沉默甲状腺基因中的关系以及与癌变的关系也将在细胞系中进行研究。在这些研究中，将使用特定的激酶抑制剂和癌蛋白和siRNAs的细胞转染法来改变MAPK途径的活性。甲状腺癌中最常见的致癌事件BRAF突变及其相关的MAPK通路异常在甲状腺特异基因的表观遗传学改变和沉默中的作用将是这些研究的主要焦点。我们期望发现关于这种最常见的内分泌癌的PTC发病机制和新的治疗靶点的重要分子信息。