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

• 批准号: 8514138
• 负责人: Lawrence S Kirschner
• 金额: $ 31.64万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 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/8514138
• 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

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（由申请人提供）：甲状腺癌是内分泌腺的最常见癌症，它也是过去20年发病率最高的癌症。分化的上皮甲状腺癌根据其组织病理学外观分为两种亚型。甲状腺乳腺癌（PTC）约占病例的80％，而卵泡甲状腺癌（FTC）占其余大部分。尽管FTC不太常见，但由于其侵略性行为和早期转移，它与较差的预后有关。有两种常染色体显性肿瘤综合征，患者患甲状腺病理的风险增加：Carney Complex（CNC）和Cowden综合征（CS）。在遗传水平上，CNC是由PRKAR1A肿瘤抑制剂突变引起的，而CS是由PTEN肿瘤抑制剂突变引起的。这些突变分别导致PKA和PI3K-AKT信号通路的多动症。在甲状腺中，众所周知，PKA从甲状腺刺激激素（TSH）下游发出信号，并且流行病学证据将TSH的增加与甲状腺癌的风险增加联系在一起。我的实验室一直在研究与PRKAR1A/PRKAR1A突变相关的肿瘤发生，并且我们最近产生了PRKAR1A甲状腺特异性KO小鼠，该小鼠在1年内在> 40％的动物中产生了FTC。此外，我们已经建立了证据表明，PKA激活（通过PRKAR1A KO）和AKT（通过PTEN KO）具有侵略性和转移性FTC，这与人类疾病具有显着相似之处。基于我们对这些模型的初步表征，我们假设PKA信号在卵泡甲状腺癌的发展中起着核心作用。这些肿瘤的行为取决于PKA与细胞中其他信号级联反应的相互作用，以抑制或促进癌变和/或转移。为了检验这一假设，我们提出了三个相互关联的研究途径。首先，尽管我们的初步数据表明甲状腺中的PKA激活具有致癌性，但多次先前的研究表明，TSH刺激（​​激活PKA和其他途径）并非如此。在AIM 1中，我们将确定TSH激活的非PKA途径，从而抑制PKA产生甲状腺癌的能力。其次，AIM 2中的实验将阐明PRKAR1A失活与PTEN损失的分子基础，从而产生侵略性的转移性FTC表型。该目标将包括检查人类FTC队列，以确定是否观察到相似的信号改变。在AIM 3中，我们将基于小鼠和人FTC的初步数据，表明MTOR激活发生在癌变期间。我们将表征MTOR蛋白及其伴侣的FTC特异性同工型，并探测MTOR激活的机理。这些数据将用于在大量人类肿瘤中驱动这些相同过程的分子分析。总体而言，拟议的研究应为卵泡甲状腺癌的生物学提供新的见解，并为开发这种疾病的临床治疗方式铺平道路。