Delineation, functional validation, and bioinformatic evaluation of gene expression in thyroid follicular carcinomas with the PAX8-PPARG translocation
Delineation, functional validation, and bioinformatic evaluation of gene expression in thyroid follicular carcinomas with the PAX8-PPARG translocation
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DOI：
10.1158/1078-0432.ccr-05-2039
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发表时间：
2006-04-01
影响因子：
11.5
通讯作者：
Koenig, RJ
中科院分区：
文献类型：
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作者：
Giordano, TJ;Au, AYM;Koenig, RJ
滤泡性甲状腺癌的一个亚组包含平衡易位t（2;3）（q13;p25），其导致配对盒基因8（PAX 8）和过氧化物酶体增殖物激活受体γ（PPARG）基因的融合，伴随PAX 8-PPAR γ融合蛋白PPFP的表达。PPFP被认为通过其作为野生型PPAR γ的显性负性抑制剂的机制促进肿瘤形成。为了更好地了解这种类型的滤泡癌，我们使用一组滤泡癌沿着与其他常见甲状腺肿瘤的DNA微阵列生成了全局基因表达谱，并使用这些数据推导出PPFP阳性肿瘤的基因表达谱特征。瞬时转染试验使用四个基因的启动子，其表达与易位高度相关，表明每个都可以被PPFP激活。与PAX 8或PPAR γ相比，PPFP具有独特的转录活性，尽管它有可能以与PAX 8或PPAR γ定性相似的方式发挥作用，这取决于启动子和细胞环境。生物信息学分析显示，PPFP阳性滤泡癌中表达增加的基因包括已知的PPAR靶基因;参与脂肪酸、氨基酸和碳水化合物代谢的基因; microRNA靶基因;和染色体3 p上的基因。这些结果对这些滤泡状癌的肿瘤发生机制有一定的意义。
A subset of follicular thyroid carcinomas contains a balanced translocation, t(2;3) (q13;p25), that results in fusion of the paired box gene 8 (PAX8) and peroxisome proliferator-activated receptor gamma (PPARG) genes with concomitant expression of a PAX8-PPAR gamma fusion protein, PPFP. PPFP is thought to contribute to neoplasia through a mechanism in which it acts as a dominant-negative inhibitor of wild-type PPAR gamma. To better understand this type of follicular carcinoma, we generated global gene expression profiles using DNA microarrays of a cohort of follicular carcinomas along with other common thyroid tumors and used the data to derive a gene expression profile characteristic of PPFP-positive tumors. Transient transfection assays using promoters of four genes whose expression was highly associated with the translocation showed that each can be activated by PPFP. PPFP had unique transcriptional activities when compared with PAX8 or PPAR gamma, although it had the potential to function in ways qualitatively similar to PAX8 or PPAR gamma depending on the promoter and cellular environment. Bioinformatics analyses revealed that genes with increased expression in PPFP-positive follicular carcinomas include known PPAR target genes; genes involved in fatty acid, amino acid, and carbohydrate metabolism; microRNA target genes; and genes on chromosome 3p. These results have implications for the neoplastic mechanism of these follicular carcinomas.