Molecular Events in the PI3K/Akt Pathway in Thyroid Cancer

简介（申请人提供）：甲状腺癌是最常见的内分泌恶性肿瘤，近年来发病率迅速上升。需要开发更有效的癌症管理策略，并且需要更好地了解其分子机制。PI3K/Akt通路最近被认为是甲状腺癌分子紊乱的主要来源。特别是，在这一途径内或与之相关的遗传和表观遗传改变及其关系，在很大程度上尚未被探索，可以想象是甲状腺癌发病机制中的关键分子事件。因此，我们提出四个特定目标来验证我们的中心假设，即重要基因（如肿瘤抑制基因、甲状腺碘处理基因和癌基因）甲基化改变与PI3K/Akt通路的耦合是甲状腺癌发病的基本机制。在Specific Aim 1中，我们将扩展我们最近发现的在间变性甲状腺癌中激活PI3K/Akt通路最有效的几个关键遗传改变，在大量滤泡性和乳头状甲状腺癌中探索它们，为PI3K/Akt通路在甲状腺癌中的一般作用建立遗传基础。类似于我们之前发现的与MAP激酶通路相关的异常基因甲基化，以及我们最近发现的甲状腺癌中一些基因甲基化与PI3K/Akt通路相关的发现，我们将在Specific Aim 2中研究，CpG甲基化微阵列分析揭示了PI3K/Akt通路中主要遗传改变与已知肿瘤抑制基因和甲状腺碘处理基因甲基化的关系，以及PI3K/Akt通路上潜在的新型高甲基化肿瘤抑制基因和低甲基化癌基因的关系。我们进一步假设，如果PI3K/Akt通路的遗传和表观遗传改变或与之相关在甲状腺癌发病机制中起重要作用，那么它们可能与甲状腺癌较差的临床病理结果相关。这将在特异性目标3中通过检查这些遗传和表观遗传改变与甲状腺癌临床病理结果的相关性来进行测试，这一策略可以揭示诊断和预后分子标记。我们最终假设，由于PI3K/Akt通路信号异常，甲基化和基因表达的改变可能通过抑制该通路而可逆，这一策略可能具有重要的治疗潜力。这将在Specific Aim 4中通过功能性操纵PI3K/Akt信号，随后检查甲状腺癌细胞系中选定功能重要基因的甲基化和表达的变化来验证。这是一项新颖的研究，首次研究了PI3K/Akt通路中的遗传和表观遗传分子事件及其作为甲状腺癌发病的基本分子机制的关系。根据所建议的策略，重点研究选定的遗传和表观遗传改变，并利用PI经验丰富的实验室，为该项目配备了最先进的专业知识和设备，预计将成功完成所建议的研究。这将为甲状腺癌发病机制的分子机制提供关键见解，并揭示新的诊断和预后分子标记和治疗靶点，以改善当前甲状腺癌患者的管理。公共卫生相关性：甲状腺癌是内分泌系统最常见的恶性肿瘤，在美国发病率迅速上升。在甲状腺癌的治疗中遇到了几个主要的临床障碍，需要更有效的策略来克服，这些策略可以最好地基于对这种癌症发病机制的分子机制的理解。该新项目旨在探索PI3K/Akt通路的遗传和表观遗传改变，有望对甲状腺癌发病的分子机制产生重要见解，并发现新的分子标记和治疗靶点，以改善甲状腺癌患者的管理。

DESCRIPTION (provided by applicant): Thyroid cancer is the most common endocrine malignancy, with a rapidly rising incidence in recent years. Development of more effective management strategies for this cancer is needed and requires better understanding of its molecular mechanisms. The PI3K/Akt pathway has recently emerged as a major source of molecular derangements in thyroid cancer. In particular, genetic and epigenetic alterations within or linked to this pathway and their relationships, which have been largely unexplored, are conceivably critical molecular events in the pathogenesis of thyroid cancer. Consequently, we propose to pursue four Specific Aims to test our central hypothesis that coupling of altered methylation of important genes (e.g., tumor suppressor genes, thyroid iodide-handling genes, and oncogenes) to the PI3K/Akt pathway driven by its genetic alterations is a fundamental mechanism in thyroid cancer pathogenesis. In Specific Aim 1, we will extend our recent findings of several key genetic alterations that are most effective in activating the PI3K/Akt pathway in anaplastic thyroid cancer to explore them in a large set of follicular and papillary thyroid cancers to establish the genetic basis for a general role of the PI3K/Akt pathway in thyroid cancer. Analogous to our previous findings of aberrant gene methylation linked to the MAP kinase pathway and with our recent findings on the link of methylation of some genes to the PI3K/Akt pathway in thyroid cancer, we will investigate, in Specific Aim 2, the relationship of major genetic alterations in the PI3K/Akt pathway with methylation of known tumor suppressor and thyroid iodide-handling genes as well as potentially novel hypermethylated tumor suppressor genes and hypomethylated oncogenes coupled to the PI3K/Akt pathway that are revealed by CpG methylation microarray analysis. We further hypothesize that if the genetic and epigenetic alterations in, or linked to, the PI3K/Akt pathway are important in thyroid cancer pathogenesis, they are likely to be associated with poorer clinicopathological outcomes of thyroid cancer. This will be tested in Specific Aim 3 by examining the correlation of these genetic and epigenetic alterations with clinicopathological outcomes of thyroid cancer, a strategy that can reveal diagnostic and prognostic molecular markers. We finally hypothesize that altered methylation and, hence, expression of genes, as a consequence of aberrant PI3K/Akt pathway signaling, may be reversible by suppressing this pathway, a strategy that may have important therapeutic potential. This is to be tested in Specific Aim 4 by functionally manipulating the PI3K/Akt signaling and subsequently examining the change in methylation and expression of selected functionally important genes in thyroid cancer cell lines. This is a novel proposal that for the first time investigates both genetic and epigenetic molecular events in the PI3K/Akt pathway and their relationship as a fundamental molecular mechanism in thyroid cancer pathogenesis. With the proposed strategy to focus on selected genetic and epigenetic alterations and with the experienced laboratory of the PI that is equipped with state-of-the-art expertise and equipments for this project, successful completion of the proposed studies is expected, which should produce key insights into the molecular mechanisms of thyroid cancer pathogenesis and uncover novel diagnostic and prognostic molecular markers and therapeutic targets to improve the current management of patients with thyroid cancer. PUBLIC HEALTH RELEVANCE: Thyroid cancer is the most common malignancy of the endocrine system, with a rapidly rising incidence in the United States. Several major clinical obstacles are encountered in the management of thyroid cancer, demanding more effective strategies to overcome that can be best based on the understanding of the molecular mechanisms in the pathogenesis of this cancer. This novel project is proposed to explore particularly genetic and epigenetic alterations in the PI3K/Akt pathway and is expected to produce important insights into the molecular mechanisms of thyroid cancer pathogenesis and uncover novel molecular markers and therapeutic targets to improve the management of patients with thyroid cancer.