Thyroid Hormone Receptors in Health and Disease

健康和疾病中的甲状腺激素受体

基本信息

批准号：
7732927
负责人：
SHEUE-YANN CHENG
金额：
$ 132.63万
依托单位：
DIVISION OF BASIC SCIENCES - NCI
依托单位国家：
美国
项目类别：
财政年份：
资助国家：
美国
起止时间：
至
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/7732927
关键词：
1-Phosphatidylinositol 3-Kinase 70-kDa Ribosomal Protein S6 Kinases AKT Signaling Pathway Adverse effects Age Apoptosis Apoptotic BAD gene Bad protein Basic Science Binding Cell Proliferation Cell physiology Cells Complex Cyclin D1 Cyclin-Dependent Kinases DNA Sequence Development Diagnosis Differentiation and Growth Disease Distant Metastasis Follicular thyroid carcinoma Gelatinase A Gene Expression Gene Targeting Genes Genetic Genetic Transcription Growth Health Hereditary Disease Human In Vitro Intervention LY294002 Malignant Neoplasms Malignant neoplasm of thyroid Mediating Metastatic Lesion Molecular Molecular Target Mus Mutant Strains Mice Mutate Mutation Oncogenic Pathogenesis Pathway interactions Pattern Pituitary Gland Pituitary Neoplasms Play Proto-Oncogene Proteins c-akt Regulation Resistance Role Signal Pathway Signal Transduction Sirolimus THRA gene THRB gene Testing Thyroid Gland Thyroid Hormone Receptor Thyroid Hormone Receptor Beta Thyroid Hormones Thyroid Stimulating Hormone Secreting Pituitary Gland Adenoma Thyroid carcinoma Thyrotropin Title Translations Triiodothyronine Wild Type Mouse base beta catenin carcinogenesis caspase-3 cell motility disorder prevention in vivo inhibitor/antagonist kinase inhibitor mouse model mutant neoplastic cell non-genomic novel novel therapeutics pre-clinical promoter receptor binding therapeutic target thyroid neoplasm tool tumor growth tumorigenesis

项目摘要

Significant new advances in 2007-2008 are highlighted below. Phosphatidylinositol 3-kinase is a potential molecular target for the treatment of thyroid cancer Aberrant activation of the phosphatidylinositol 3-kinase (PI3K)-AKT/protein kinase B signaling pathway has been associated with multiple human cancers, including thyroid cancer. Recently we showed that, similar to human thyroid cancer, the PI3K-AKT pathway is overactivated in both the thyroid and metastatic lesions of a mouse model of follicular thyroid carcinoma (TRbetaPV/PV mice). This TRbetaPV/PV mouse harbors a knockin mutant thyroid hormone receptor beta gene (TRbetaPV mutant) that spontaneously develops thyroid cancer and distant metastasis similar to human follicular thyroid cancer. That the activation of the PI3K-AKT signaling contributes to thyroid carcinogenesis raised the possibility that this pathway could be a potential therapeutic target in follicular thyroid carcinoma. We therefore tested this possibility by treating TRbetaPV/PV mice with LY294002 (LY), a potent and specific PI3K inhibitor, and evaluating the effect of LY on the spontaneous development of thyroid cancer. LY treatment inhibited the AKT-mammalian target of rapamycin (mTOR)-p70S6K signaling, and it decreased cyclin D1 and increased p27Kip1 expression to inhibit thyroid tumor growth and reduce tumor cell proliferation. LY treatment increased caspase 3 and decreased phosphorylated BAD to induce apoptosis. In addition, LY treatment reduced the AKT-matrix metalloproteinase 2 signaling to decrease cell motility to block metastatic spread of thyroid tumors. Thus, these altered signaling pathways converged effectively to prolong survival of TRbetaPV/PV mice treated with LY. No significant adverse effects were observed for wild type mice treated similarly with LY. Our study provides the first preclinical evidence for the in vivo efficacy for LY in the treatment of follicular thyroid cancer. Thus, PI3K is a potential molecular target to treat thyroid cancer. Phosphatidylinositol 3-kinase is a potential molecular target for the treatment of pituitary tumors Thyroid-stimulating hormone (TSH)-secreting pituitary tumors (TSHomas) are pituitary tumors that constitutively secrete TSH. Molecular mechanisms underlying this abnormality are largely undefined. As TRbetaPV/PV mice age, they spontaneously develop TSHomas. Using this mouse model, we investigated the role of the PI3K-AKT signaling pathway in the pathogenesis of TSHomas. Concurrent with aberrant growth of pituitaries, AKT and its downstream effectors mammalian target rapamycin (mTOR) and p70S6Kwere activated to contribute to increased cell proliferation and pituitary growth. In addition, activation of AKT led to decreased apoptosis by inhibiting pro-apoptotic activity of BAD, further contributing to the aberrant cell proliferation. These results suggest an activated PI3K-AKT pathway could underscore tumorigenesis, raising the possibility that this pathway could be a potential therapeutic target in TSHomas. Indeed, TRbetaPV/PV mice treated with a PI3K specific inhibitor, LY294002 (LY), showed a significant decrease in pituitary growth. The pro-growth signaling via AKT-mTOR-p70S6K and cyclin D1/cyclin-dependent kinase (CDK4) were inhibited and pro-apoptotic activity of BAD was increased by LY treatment. Thus, activation of the PI3K-AKT pathway mediates, at least in part, the aberrant pituitary growth, and the intervention of this signaling pathway presents a novel therapeutic opportunity for TSHomas. Regulation of beta-catenin by a novel nongenomic action of thyroid hormone beta receptor Analysis of altered gene expression patterns during thyroid carcinogenesis of TRbetaPV/PV mice showed that beta-catenin, which plays a critical role in oncogenesis, was highly elevated in thyroid tumors. We sought to understand the molecular basis underlying aberrant accumulation of beta-catenin by mutations of TRbeta in vivo . Cell-based studies showed that T3 induced the degradation of beta-catenin in cells expressing TRbeta via proteasomal pathways. In contrast, no T3-induced degradation occurred in cells expressing PV. In vitro binding studies and cell-based analyses revealed that beta-catenin physically associated with the unliganded TRbeta or PV. However, in the presence of T3, beta-catenin was dissociated from TRbeta/beta-catenin complexes, but not from PV/beta-catenin complexes. Beta-catenin signaling was repressed by T3 in TRbeta-expressing cells through decreasing beta-catenin-mediated transcription activity and target gene expression, whereas sustained beta-catenin signaling was observed in PV-expressing cells. The stabilization of beta-catenin, via association with a mutated TRbeta, represents a novel activating mechanism of the oncogenic beta-catenin that could contribute to thyroid carcinogenesis in TRbetaPV/PV mice.

下面强调了2007 - 2008年的重大新进展。磷脂酰肌醇3-激酶是治疗甲状腺癌异常激活磷脂酰肌醇3-激酶（PI3K）-AKT/蛋白质激酶B信号传导途径的潜在分子靶标，与包括甲状腺癌在内的多种人类癌症有关。最近，我们表明，与人类甲状腺癌相似，PI3K-AKT途径在卵泡甲状腺癌小鼠模型的甲状腺和转移性病变中都过度活化。这款TRBETAPV/PV小鼠拥有敲击蛋白突变体甲状腺激素受体β基因（TRBETAPV突变体）自发发展甲状腺癌和类似于人卵泡甲状腺癌的远处转移。 PI3K-AKT信号的激活有助于甲状腺癌发生，这使该途径可能是卵泡甲状腺癌的潜在治疗靶标。因此，我们通过用LY294002（LY）（一种有效的特定PI3K抑制剂）处理TRBETAPV/PV小鼠来测试这种可能性，并评估LY对甲状腺癌自发发展的影响。 LY治疗抑制了雷帕霉素（MTOR）-P70S6K信号的AKT哺乳动物靶标，并降低了细胞周期蛋白D1并增加了P27KIP1表达以抑制甲状腺肿瘤的生长并减少肿瘤细胞增殖。 Ly处理增加了胱天冬酶3，并减少了磷酸化的坏处以诱导凋亡。此外，LY处理减少了Akt-Matrix金属蛋白酶2信号传导，以降低细胞运动性，以阻止甲状腺肿瘤的转移性扩散。因此，这些改变的信号通路有效地融合了用LY处理的TRBETAPV/PV小鼠的生存。对于与LY类似处理的野生型小鼠，未观察到明显的不良反应。我们的研究提供了对卵泡甲状腺癌治疗体内功效的第一个临床前证据。因此，PI3K是治疗甲状腺癌的潜在分子靶标。磷脂酰肌醇3-激酶是治疗垂体肿瘤甲状腺刺激激素（TSH） - 定位垂体肿瘤（TSHOMAS）的潜在分子靶标，是垂体肿瘤，是组成性分泌TSH的垂体肿瘤。这种异常的分子机制在很大程度上是不确定的。随着TRBETAPV/PV小鼠的年龄，它们会自发发展Tshomas。使用该小鼠模型，我们研究了PI3K-AKT信号通路在Tshomas发病机理中的作用。同时，垂体，AKT及其下游效应子哺乳动物靶雷霉素（MTOR）和P70S6KWERE的异常生长，从而有助于增加细胞增殖和垂体生长。此外，AKT的激活通过抑制不良的凋亡活性而导致凋亡减少，进一步导致异常细胞增殖。这些结果表明，活化的PI3K-AKT途径可能强调肿瘤发生，从而增加了该途径可能是TSHOMAS中潜在的治疗靶标的可能性。实际上，用PI3K特异性抑制剂LY294002（LY）处理的TRBETAPV/PV小鼠显示垂体生长显着降低。通过AKT-MTOR-P70S6K和细胞周期蛋白D1/Cyclin依赖性激酶（CDK4）通过AKT-MTOR-P70S6K和细胞周期蛋白D1/Cyclin prowth的信号传导被抑制，并且通过LY治疗增加了不良凋亡活性。因此，PI3K-AKT途径的激活至少部分介导了异常的垂体生长，而该信号通路的干预为TSHOMAS带来了新的治疗机会。甲状腺激素β受体受体分析在甲状腺激素表达模式的改变的基因表达模式对TRBETAPV/PV小鼠的甲状腺激素β受体分析对β-蛋白的调节表明，β-蛋白在甲状腺肿瘤中起着高度升高。我们试图了解通过体内Trbeta突变的β-catenin的分子基础的异常积累。基于细胞的研究表明，T3诱导通过蛋白酶体途径表达TRBETA的细胞中β-catenin的降解。相反，在表达PV的细胞中未发生T3诱导的降解。体外结合研究和基于细胞的分析表明，β-catenin与非配体的TRBETA或PV物理相关。然而，在存在T3的情况下，β-catenin与Trbeta/beta-catenin络合物分离，但不能与PV/Beta-catenin复合物分离。 T3在表达TRBETA的细胞中通过降低β-catenin介导的转录活性和靶基因表达来抑制了β-连环蛋白信号传导，而在表达PV表达细胞中持续的β-catenin信号传导。通过与突变的TRBETA结合，β-catenin的稳定性代表了致癌β-catenin的一种新型激活机制，可以在TRBETAPV/PV小鼠中有助于甲状腺癌发生。

项目成果

期刊论文数量（34）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Alterations in genomic profiles during tumor progression in a mouse model of follicular thyroid carcinoma.

滤泡性甲状腺癌小鼠模型肿瘤进展过程中基因组谱的变化。

DOI：
10.1093/carcin/bgg111
发表时间：
2003
期刊：
Carcinogenesis
影响因子：
4.7
作者：
Ying,Hao;Suzuki,Hideyo;Furumoto,Hiroko;Walker,Robert;Meltzer,Paul;Willingham,MarkC;Cheng,Sheue-Yann
通讯作者：
Cheng,Sheue-Yann

Chromosomal aberrations in cell lines derived from thyroid tumors spontaneously developed in TRbetaPV/PV mice.

TRbetaPV/PV 小鼠中甲状腺肿瘤细胞系自发产生染色体畸变。