Delineation, functional validation, and bioinformatic evaluation of gene expression in thyroid follicular carcinomas with the PAX8-PPARG translocation.
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-PPARgamma 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 PPARgamma. 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 PPARgamma, although it had the potential to function in ways qualitatively similar to PAX8 or PPARgamma 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; micro-RNA target genes; and genes on chromosome 3p. These results have implications for the neoplastic mechanism of these follicular carcinomas.
Giordano
Thomas J
TJ
Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan, USA.
Au
Amy Y M
AY
Kuick
Rork
R
Thomas
Dafydd G
DG
Rhodes
Daniel R
DR
Wilhelm
Kenneth G
KG
Vinco
Michelle
M
Misek
David E
DE
Sanders
Donita
D
Zhu
Zhaowen
Z
Ciampi
Raffaele
R
Hanash
Samir
S
Chinnaiyan
Arul
A
Clifton-Bligh
Roderick J
RJ
Robinson
Bruce G
BG
Nikiforov
Yuri E
YE
Koenig
Ronald J
RJ
D018263:Adenocarcinoma, Follicular / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D002889:Chromosomes, Human, Pair 2 / Q000235:genetics; D002893:Chromosomes, Human, Pair 3 / Q000235:genetics; D019295:Computational Biology; D020869:Gene Expression Profiling; D006801:Humans; D015514:Oncogene Proteins, Fusion / Q000096:biosynthesis / Q000235:genetics*; D000072636:PAX8 Transcription Factor; D047495:PPAR gamma / Q000235:genetics* / Q000378:metabolism; D051761:Paired Box Transcription Factors / Q000235:genetics* / Q000378:metabolism; D025341:Principal Component Analysis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013964:Thyroid Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D014178:Translocation, Genetic
D015514:Oncogene Proteins, Fusion; D000072636:PAX8 Transcription Factor; C083325:PAX8 protein, human; D047495:PPAR gamma; D051761:Paired Box Transcription Factors