PKA and follicular thyroid carcinogenesis: Roles of interacting pathways

PKA 和滤泡性甲状腺癌发生：相互作用途径的作用

基本信息

批准号：
8627151
负责人：
Lawrence S Kirschner
金额：
$ 30.69万
依托单位：
OHIO STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-04-01 至 2018-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8627151
关键词：
AKT Signaling Pathway Accounting Aggressive behavior Animals Appearance Atrial myxoma with lentigines Behavior Biology Brain Neoplasms Breast Hamartoma Cancer Etiology Canis familiaris Cattle Cells Clinical Treatment Complex Cyclic AMP-Dependent Protein Kinases Data Detection Development Disease Drug Targeting Endocrine Epidemiology Epithelial Exhibits Follicular thyroid carcinoma GTP-Binding Proteins Gene Proteins Genetic Glean Grant Homeostasis Human Human Cell Line Hyperactive behavior Hyperplasia In Vitro Incidence Inherited Investigation Laboratories Lead Lesion Light Malignant Neoplasms Malignant neoplasm of thyroid Modeling Molecular Molecular Analysis Multiple Hamartoma Syndrome Mus Mutation Myxoma Neoplasm Metastasis Neoplasms Neurilemmoma PTEN gene Papillary thyroid carcinoma Pathogenesis Pathology Pathway interactions Patients Phenotype Play Predisposition Process Protein Isoforms Proto-Oncogene Proteins c-akt Raptors Rare Diseases Rattus Risk Role Signal Pathway Signal Transduction Skin Pigmentation Syndrome System Testing Therapeutic Thyroid Gland Thyrotropin Tissues Tumor Suppressor Proteins Undifferentiated United States adenoma base cancer type carcinogenesis cell type cohort disease phenotype follicular epithelial cell genetic analysis human FRAP1 protein human disease in vivo insight interest mTOR protein malignant endocrine gland neoplasm mouse model outcome forecast prevent public health relevance research study tissue culture tumor tumor progression tumorigenesis

项目摘要

DESCRIPTION (provided by applicant): Thyroid cancer is the most common cancer of the endocrine glands, and it is also the cancer with the highest increase in incidence over the past 20 years. Differentiated epithelial thyroid cancers are divided into two subtypes based on their histopathological appearance. Papillary thyroid cancer (PTC) accounts for about 80% of cases, whereas follicular thyroid cancer (FTC) accounts for the majority of the remainder. Although FTC is less common, it is associated with a poorer prognosis because of its aggressive behavior and early metastasis. There are two autosomal dominant tumor syndromes in which patients are at increased risk for this thyroid pathology: Carney Complex (CNC) and Cowden syndrome (CS). At the genetic level, CNC is caused by mutations in the PRKAR1A tumor suppressor whereas CS is caused by mutations in the PTEN tumor suppressor. These mutations lead to hyperactivity of the PKA and PI3K-AKT signaling pathways, respectively. In the thyroid, PKA is known to signal downstream from thyroid stimulating hormone (TSH), and epidemiologic evidence connects increased TSH to increased risk for thyroid cancer. My laboratory has been studying tumorigenesis associated with mutations of PRKAR1A/Prkar1a, and we have recently generated Prkar1a thyroid specific KO mice that develop FTC within 1 year in >40% of animals. Further, we have developed evidence that mice with activation of both PKA (via Prkar1a KO) and Akt (via Pten KO) have aggressive and metastatic FTC which has significant similarities to the human disease. Based on our preliminary characterization of these models, we hypothesize that PKA signaling plays a central role in the development of follicular thyroid cancer. The behavior of these tumors depends on the interaction of PKA with other signaling cascades in the cell to either restrain or promote carcinogenesis and/or metastasis. To test this hypothesis, we propose three inter-related avenues of investigation. First, although our preliminary data demonstrates that PKA activation in the thyroid is carcinogenic, multiple prior studies have shown that TSH stimulation (which activates PKA and other pathways) is not. In Aim 1, we will identify the non-PKA pathways activated by TSH that suppress PKA's ability to produce thyroid cancers. Second, the experiments in Aim 2 will elucidate the molecular basis by which inactivation of Prkar1a combines with loss of Pten to produce an aggressive metastatic FTC phenotype. This Aim will include examination of a cohort of human FTC to determine if similar signaling alterations are observed. In Aim 3, we will build on preliminary data from both mouse and human FTCs indicating that mTOR activation occurs during carcinogenesis. We will characterize FTC-specific isoforms of the mTOR protein and its partners and probe the mechanism of mTOR activation. These data will be used to drive molecular analysis of these same processes in a large cohort of human tumors. Overall, the proposed studies should provide new insights into the biology of follicular thyroid cancers and help pave the way for the development of new modes of clinical treatment of this disease.

描述（申请人提供）：甲状腺癌是最常见的内分泌腺癌症，也是近20年来发病率增幅最高的癌症。分化型上皮性甲状腺癌根据其组织病理学外观分为两种亚型。甲状腺乳头状癌 (PTC) 约占病例的 80%，而滤泡性甲状腺癌 (FTC) 则占其余病例的大部分。尽管 FTC 不太常见，但由于其侵袭性行为和早期转移，其预后较差。有两种常染色体显性肿瘤综合征，患者患这种甲状腺病理的风险增加：卡尼综合征 (CNC) 和考登综合征 (CS)。在基因水平上，CNC是由PRKAR1A肿瘤抑制基因突变引起的，而CS是由PTEN肿瘤抑制基因突变引起的。这些突变分别导致 PKA 和 PI3K-AKT 信号通路过度活跃。在甲状腺中，已知 PKA 会向促甲状腺激素 (TSH) 下游发出信号，流行病学证据表明 TSH 升高与甲状腺癌风险增加有关。我的实验室一直在研究与 PRKAR1A/Prkar1a 突变相关的肿瘤发生，我们最近培育了 Prkar1a 甲状腺特异性 KO 小鼠，这些小鼠在 1 年内使超过 40% 的动物出现 FTC。此外，我们还发现证据表明，同时激活 PKA（通过 Prkar1a KO）和 Akt（通过 Pten KO）的小鼠具有侵袭性和转移性 FTC，这与人类疾病具有显着相似性。基于我们对这些模型的初步表征，我们假设 PKA 信号在滤泡性甲状腺癌的发展中发挥核心作用。这些肿瘤的行为取决于 PKA 与细胞中其他信号级联的相互作用，以抑制或促进癌发生和/或转移。为了检验这一假设，我们提出了三种相互关联的调查途径。首先，虽然我们的初步数据表明甲状腺中的 PKA 激活具有致癌性，但多项先前研究表明 TSH 刺激（激活 PKA 和其他途径）不会致癌。在目标 1 中，我们将确定由 TSH 激活的非 PKA 途径，这些途径抑制 PKA 产生甲状腺癌的能力。其次，目标 2 中的实验将阐明 Prkar1a 失活与 Pten 缺失相结合产生侵袭性转移 FTC 表型的分子基础。该目标将包括对人类 FTC 队列进行检查，以确定是否观察到类似的信号传导改变。在目标 3 中，我们将基于小鼠和人类 FTC 的初步数据，表明 mTOR 激活发生在致癌过程中。我们将表征 mTOR 蛋白及其伴侣的 FTC 特异性亚型，并探讨 mTOR 激活机制。这些数据将用于驱动对大量人类肿瘤中这些相同过程的分子分析。总体而言，拟议的研究应该为滤泡性甲状腺癌的生物学提供新的见解，并有助于为该疾病临床治疗新模式的开发铺平道路。