Expression profiling reveals a distinct transcription signature in follicular thyroid carcinomas with a PAX8-PPARγ fusion oncogene

Lui, Weng‐Onn; Foukakis, Theodoros; Lidén, Johan; Thoppe, Srinivasan R.; Dwight, Trisha; Höög, Anders; Zedenius, Jan; Wallin, Göran; Reimers, Mark; Larsson, Catharina

doi:10.1038/sj.onc.1208135

Cited by 67 publications

(44 citation statements)

References 37 publications

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“…This unexpected finding supports recent speculation that FC with pax8-ppar 1 and FC with ras mutation constitute distinct biological entities (Nikiforova et al 2003, Lui et al 2005. Experimental data in human thyroid epithelial cells show that mutant RAS induces self-limited proliferation without loss of differentiation (Gire & Wynford-Thomas 2000).…”

Section: Discussionsupporting

confidence: 75%

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Expression of tpo mRNA in thyroid tumors: quantitiative PCR analysis and correlation with alterations of ret, Braf , ras and pax8 genes

Cristofaro¹,

Silvy²,

Lanteaume³

et al. 2006

Endocr Relat Cancer

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Expression of tpo mRNA in thyroid tumors: quantitiative PCR analysis and correlation with alterations of ret , Braf , ras and pax 8 genes AbstractImmunocytochemistry (ICC) of thyroid peroxidase (TPO) using the monoclonal antibody MoAb47 has been used as malignancy marker on thyroid fine needle aspiration. However, little is known about the fate of TPO in thyroid carcinoma. We performed a qualitative PCR (Q-PCR) analysis to measure the expression of variants of tpo mRNA in 13 normal tissue samples, 30 benign tumors (BT), 21 follicular carcinomas (FC), 20 classical papillary carcinomas (PCc), 12 follicular variants of papillary carcinomas (PCfv) and nine oncocytic carcinomas (OC). We also studied mutations involving the ras, Braf, ret or pax8 genes. Results of Q-PCR were closely correlated with those of ICC (P < 0:0001; R ¼ 0.59) and showed that overall tpo expression was lower in all carcinomas than in normal and BT (P < 0:05). The ratio tpo2 or tpo3 to tpo1 was inversed in follicular tumors. Genetic mutations were observed in 90% of PCc, 61.9% of FC, 41.7% of PCfv, 0% of OC and 10% in BT. pax8-ppar 1 rearrangement was correlated with qualitative changes in tpo mRNA (P < 0:01). These results confirmed the decrease of TPO expression in 97% of thyroid carcinomas regardless of histological type and the overexpression of shorter splice variants in follicular tumors. Both reduction in quantity of TPO and impairment of its maturation process could account for the atypical immunohistochemical reaction of MoAb47 with TPO.

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Section: Discussionsupporting

confidence: 75%

“…Expression profile analysis of FC displaying pax8-ppar 1 fusion oncogene demonstrated impairment of ribosomal proteins and of translation-associated genes that could explain disruption of the protein maturation process (Lui et al 2005). Further study will be needed to determine the exact effect of pax8-ppar 1 on tpo mRNA maturation.…”

Section: Discussionmentioning

confidence: 99%

Expression of tpo mRNA in thyroid tumors: quantitiative PCR analysis and correlation with alterations of ret, Braf , ras and pax8 genes

Cristofaro¹,

Silvy²,

Lanteaume³

et al. 2006

Endocr Relat Cancer

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“…A common mutation in follicular thyroid tumors occurs in PAX8/ PPARg rearrangement, resulting in a putative downregulation of the wild-type PPARg activity via a dominant negative mechanism (Kroll et al, 2000;Dwight et al, 2003;Gregory et al, 2004;McIver et al, 2004;Lui et al, 2005). This suggested that PPARg may act as a tumor suppressor gene (Kroll et al, 2000;Lui et al, 2005).…”

Section: Introductionmentioning

confidence: 99%

“…This suggested that PPARg may act as a tumor suppressor gene (Kroll et al, 2000;Lui et al, 2005). This mutation has not been identified in the more frequent occurring papillary carcinoma (B80% of all thyroid cancers) or the rarer, but deadly anaplastic thyroid carcinoma (ATC).…”

Section: Introductionmentioning

confidence: 99%

Novel high-affinity PPARγ agonist alone and in combination with paclitaxel inhibits human anaplastic thyroid carcinoma tumor growth via p21WAF1/CIP1

et al. 2005

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Peroxisomeproliferator-activated receptor gamma (PPARc) agonists demonstrate antitumor activity likely through transactivating genes that regulate cell proliferation, apoptosis, and differentiation. The PAX8/PPARc fusion oncogene, which is common in human follicular thyroid carcinomas appears to act via dominant negative suppression of wild-type PPARc, suggesting that it may be a tumor suppressor gene in thyroid cells. We have identified a novel high-affinity PPARc agonist (RS5444) that is dependent upon PPARc for its biological activity. This is the first report of this molecule and its antitumor activity. In vitro, the IC 50 for growth inhibition is B0.8 nM while anaplastic thyroid carcinoma (ATC) tumor growth was inhibited threeto fourfold in nude mice. siRNA against PPARc and a pharmacological antagonist demonstrated that functional PPARc was required for growth inhibitory activity of RS5444. RS5444 upregulated the cell cycle kinase inhibitor, p21 WAF1/CIP1 . Silencing p21 WAF1/CIP1 rendered cells insensitive to RS5444. RS5444 plus paclitaxel demonstrated additive antiproliferative activity in cell culture and minimal ATC tumor growth in vivo. RS5444 did not induce apoptosis but combined with paclitaxel, doubled the apoptotic index compared to that of paclitaxel. Our data indicate that functional PPARc is a molecular target for therapy in ATC. We demonstrated that RS5444, a thiazolidinedione (Tzd) derivative, alone or in combination with paclitaxel, may provide therapeutic benefit to patients diagnosed with ATC.

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“…116 Unfortunately, the commercial qPCR assay used to validate these findings recognises the unique exon 1 found in the ribeye transcript, and therefore the role of CtBP2 in these tumors remains to be confirmed. CtBPs are, …”

Section: Future Perspectivesmentioning

confidence: 99%

C-terminal binding proteins: Emerging roles in cell survival and tumorigenesis

Bergman

Blaydes

2006

Apoptosis

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Expression profiling reveals a distinct transcription signature in follicular thyroid carcinomas with a PAX8-PPARγ fusion oncogene

Cited by 67 publications

References 37 publications

Expression of tpo mRNA in thyroid tumors: quantitiative PCR analysis and correlation with alterations of ret, Braf , ras and pax8 genes

Expression of tpo mRNA in thyroid tumors: quantitiative PCR analysis and correlation with alterations of ret, Braf , ras and pax8 genes

Novel high-affinity PPARγ agonist alone and in combination with paclitaxel inhibits human anaplastic thyroid carcinoma tumor growth via p21WAF1/CIP1

C-terminal binding proteins: Emerging roles in cell survival and tumorigenesis

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