Peroxisome proliferator-activated receptor gamma is frequently downregulated in a diversity of sporadic nonmedullary thyroid carcinomas

Aldred, Micheala A.; Morrison, Carl; Gimm, Oliver; Hoang‐Vu, Cuong; Krause, U.; Dralle, Henning; Jhiang, Sissy; Eng, Charis

doi:10.1038/sj.onc.1206400

Cited by 57 publications

(52 citation statements)

References 20 publications

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“…While several groups have reported gene expression profiles in follicular adenomas and in follicular and papillary carcinomas (Huang et al, 2001;Aldred et al, 2003;Barden et al, 2003;Yano et al, 2004), only one similar study has been performed so far (Eszlinger et al, 2004). Our data set provides considerable new information about proteins and pathways involved in this disease, which will now be the subject of more detailed investigations.…”

Section: Discussionmentioning

confidence: 79%

“…Decreased caveolin expression has previously been observed in Tg-A2aR mice (Goffard et al, 2004) and has also been shown to be a characteristic of thyroid follicular carcinomas (Aldred et al, 2003(Aldred et al, , 2004. The decreased expression in autonomous adenomas, which are benign, noninvading tumors, certainly shows that, as for N-cadherin overexpression, underexpression of caveolins is not sufficient to confer a malignant phenotype and is not even a marker of malignancy.…”

Section: Discussionmentioning

confidence: 85%

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Gene expression in thyroid autonomous adenomas provides insight into their physiopathology

Wattel¹,

Mircescu²,

Venet³

et al. 2005

Oncogene

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The purpose of this study was to use the microarray technology to define expression profiles characteristic of thyroid autonomous adenomas and relate these findings to physiological mechanisms. Experiments were performed on a series of separated adenomas and their normal counterparts on Micromax cDNA microarrays covering 2400 genes (analysis I), and on a pool of adenomatous tissues and their corresponding normal counterparts using microarrays of 18 000 spots (analysis II). Results for genes present on the two arrays corroborated and several gene regulations previously determined by Northern blotting or microarrays in similar lesions were confirmed. Five overexpressed and 24 underexpressed genes were also confirmed by real-time RT-PCR in some of the samples used for microarray analysis, and in additional tumor specimens. Our results show: (1) a change in the cell populations of the tumor, with a marked decrease in lymphocytes and blood cells and an increase in endothelial cells. The latter increase would correspond to the establishment of a close relation between thyrocytes and endothelial cells and is related to increased N-cadherin expression. It explains the increased blood flow in the tumor; (2) a homogeneity of tumor samples correlating with their common physiopathological mechanism: the constitutive activation of the thyrotropin (TSH)/cAMP cascade; (3) a low proportion of regulated genes consistent with the concept of a minimal deviation tumor; (4) a higher expression of genes coding for specific functional proteins, consistent with the functional hyperactivity of the tumors; (5) an increase of phosphodiesterase gene expression which explains the relatively low cyclic AMP levels measured in these tumors; (6) an overexpression of antiapoptotic genes and underexpression of proapoptotic genes compatible with their low apoptosis rate; (7) an overexpression of N-cadherin and downregulation of caveolins, which casts doubt about the use of these expressions as markers for malignancy.Oncogene (2005) 24, 6902-6916.

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Section: Discussionmentioning

confidence: 79%

Section: Discussionmentioning

confidence: 85%

Gene expression in thyroid autonomous adenomas provides insight into their physiopathology

Wattel¹,

Mircescu²,

Venet³

et al. 2005

Oncogene

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“…Paclitaxel has demonstrated prolongation of life for ATC patients in a clinical trial and appears the standard of care with regards to chemotherapeutic intervention for patients diagnosed with ATC (Ain et al, 2000). Aldred et al (2003) described PPARg expression in thyroid cancer subtypes demonstrating that ATCs were positive by IHC in 9/14 cases and percentage-wise, PPARg expression was higher than any other thyroid cancer subtype. In their discussion, they noted that further studies of PPARg status in ATCs may provide insights into pathogenesis and management of ATC.…”

Section: Discussionmentioning

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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“…It has been reported that RNA expression of PPARg was frequently reduced in several types of nonmedullary thyroid cancer, including FTCs, PTCs and Hu¨rthle cell carcinomas (Aldred et al, 2003). Conversely, its expression in the tumors with a PPARg rearrangement was significantly increased, at least fourfold as compared to the non-PPARg rearranged tumors (Aldred et al, 2003).…”

Section: Ccnd1(r=085)mentioning

confidence: 98%

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

et al. 2004

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Peroxisome proliferator-activated receptor gamma is frequently downregulated in a diversity of sporadic nonmedullary thyroid carcinomas

Cited by 57 publications

References 20 publications

Gene expression in thyroid autonomous adenomas provides insight into their physiopathology

Gene expression in thyroid autonomous adenomas provides insight into their physiopathology

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

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

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