Tumor Suppressors and Differentiated Thyroid Cancer

肿瘤抑制剂和分化型甲状腺癌

• 批准号: 7117826
• 负责人: NORMAN L EBERHARDT
• 金额: $ 29.17万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-01-05 至 2009-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7117826
• 关键词: cell transformation; chimeric proteins; chromosome aberrations; clinical research; disease /disorder model; gene expression; gene targeting; genetic transcription; genetically modified animals; laboratory mouse; ligands; model design /development; oncoproteins; peroxisome proliferator activated receptor; protein structure function; thyroid neoplasm

DESCRIPTION (provided by applicant): The initiating molecular events in the most common types of thyroid cancer frequently involve chromosomal translocations, in contrast to other solid tumor types in which such events are rare. The RET/PTC rearranged oncogene accounts for the majority of radiation-induced papillary thyroid cancer (PTC) and up to 50% of sporadic PTC. An analogous chromosomal rearrangement occurs frequently (30-60%) in follicular thyroid cancer (FTC). This rearrangement involves a t(2;3)(q 13;p25) translocation, which fuses the thyroid specific transcription factor pax8 gene (chromosome 2) and the PPARgamma receptor gene (chromosome 3), resulting in the expression of a fusion protein, designated PPFP. PPFP contains a partial length pax8 and a full-length PPARgamma receptor, which is expressed under the control of the pax8 promoter in a thyroidspecific fashion. We have confirmed that almost 60% of FTC express PPFP. We have also shown that PPFP can transform Nthy-ori 3-1 thyroid cells in vitro, causing increased cell growth, decreased apoptosis, and anchorage-independent growth. PPFP also transforms NIH 3T3 cells. The inhibition of apoptosis is due in part to down-regulation of TRAIL-R2. Our findings also strongly suggest that the changes in growth and apoptosis are mediated by inhibition of wild-type PPARgamma. These data suggest that PPFP is an oncoprotein that functions in FTC tumorigenesis. In the current studies we will study the ability of PPFP to transform thyroctes in an in vivo mouse knockin model, designed to recapitulate all the genetic features of the human disease (Aim 1). In Aim 2 we will study the mechanism of PPFP's dominant negative inhibition of PPARgamma. Finally, in Aim 3 we will identify the downstream PPARgamma-dependent effector pathways that mediate PPFP's transforming properties. These studies will test the following hypotheses: (1) PPFP is an oncoprotein, resulting from chromosomal rearrangements unique to FTC, and is sufficient to transform thyroid folliciular cells in vivo. (2) PPFP is involved in the early stages of FTC tumorigenesis. (3) PPFP acts solely through dominant negative inhibition of PPARgamma. (4) The inhibitory effects of PPFP can be modulated by PPARgamma and RXR Iigand binding. (5) PPFP alters multiple PARgamma-regulated transcription pathways, which alter growth control and/or apoptosis.

描述（由申请人提供）：与其他实体瘤类型相比，最常见的甲状腺癌类型中的启动分子事件经常涉及染色体易位。 RET/PTC重新排列的癌基因占辐射诱导的甲状腺癌（PTC）的大部分，最多可占50％的零星PTC。卵泡甲状腺癌（FTC）经常发生类似的染色体重排（30-60％）。该重排涉及t（2; 3）（q 13; p25）易位，融合了甲状腺特异性转录因子PAX8基因（染色体2）和ppargamma受体基因（3染色体3），从而导致融合蛋白的表达，指定PPFP。 PPFP包含部分长度PAX8和一个全长PPARGAMMA受体，该受体以甲状腺特定的方式在PAX8启动子的控制下表达。我们已经确认，FTC Express PPFP近60％。我们还表明，PPFP可以在体外3-1甲状腺细胞转化NTHY-ORI，从而导致细胞生长增加，凋亡减少和锚固非依赖性生长。 PPFP还会改变NIH 3T3细胞。凋亡的抑制作用部分归因于TRAIL-R2的下调。我们的发现也强烈表明，生长和凋亡的变化是通过抑制野生型Ppargamma介导的。这些数据表明PPFP是一种在FTC肿瘤发生中起作用的癌蛋白。在当前的研究中，我们将研究PPFP在体内小鼠敲蛋白模型中转化甲状腺的能力，该模型旨在概括人类疾病的所有遗传特征（AIM 1）。在AIM 2中，我们将研究PPFP对Ppargamma的主要负面抑制的机制。最后，在AIM 3中，我们将确定介导PPFP转换特性的下游PPARGAMMA依赖性效应器途径。这些研究将检验以下假设：（1）PPFP是一种癌蛋白，是由FTC独有的染色体重排而产生的，足以在体内转化甲状腺卵泡细胞。 （2）PPFP参与FTC肿瘤发生的早期阶段。 （3）PPFP仅通过对PPARGAMMA的显着负面抑制作用起作用。 （4）PPARGAMMA和RXR IIGAND结合可以调节PPFP的抑制作用。 （5）PPFP改变了多个由Pargamma调节的转录途径，这些途径改变了生长控制和/或凋亡。