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（申请人提供）：甲状腺癌是内分泌腺最常见的癌症，也是近20年来发病率上升最快的癌症。分化型甲状腺上皮癌根据其组织病理学表现分为两种亚型。甲状腺乳头状癌（PTC）约占病例的80%，而滤泡性甲状腺癌（FTC）占其余病例的大部分。虽然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，其中患者的甲状腺病理风险增加：卡尼综合征（CNC）和考登综合征（CS）。在遗传水平上，CNC是由PRKAR 1A肿瘤抑制因子突变引起的，而CS是由PTEN肿瘤抑制因子突变引起的。这些突变分别导致PKA和PI 3 K-AKT信号通路的过度活跃。在甲状腺中，PKA是促甲状腺激素（TSH）的下游信号，流行病学证据将TSH增加与甲状腺癌风险增加联系起来。我的实验室一直在研究与PRKAR 1A/Prkar 1a突变相关的肿瘤发生，我们最近培育了Prkar 1a甲状腺特异性KO小鼠，这些小鼠在1年内在>40%的动物中发展为FTC。此外，我们已经发现了PKA（通过Prkar 1a KO）和Akt（通过Pten KO）激活的小鼠具有侵袭性和转移性FTC的证据，这与人类疾病具有显著的相似性。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，我们提出了三个相互关联的调查途径。首先，尽管我们的初步数据表明甲状腺中PKA的激活是致癌的，但多项先前的研究表明TSH刺激（激活PKA和其他途径）不是。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。第二，目标2中的实验将阐明Prkar 1a失活与Pten丢失相结合产生侵袭性转移性FTC表型的分子基础。该目的将包括检查一组人FTC，以确定是否观察到类似的信号传导改变。在目标3中，我们将建立在小鼠和人类FTC的初步数据基础上，这些数据表明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特异性同种型，并探索mTOR激活的机制。这些数据将用于在一个大型人类肿瘤队列中驱动这些相同过程的分子分析。总的来说，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，并有助于为开发这种疾病的临床治疗新模式铺平道路。