Underexpression of peroxisome proliferator-activated receptor (PPAR)γ in PAX8/PPARγ-negative thyroid tumours

Abstract

The expression of peroxisome proliferator-activated receptor (PPAR)g in thyroid neoplasias and in normal thyroid (NT) tissues has not been fully investigated. The objectives of the present work were: to study and compare the relative expression of PPARg in normal, benign and malignant thyroid tissues and to correlate PPARg immunostaining with clinical/pathological features of patients with thyroid cancer. We analysed the expression of PPARg in several types of thyroid tissues by reverse transcription -polymerase chain reaction (RT -PCR), interphase fluorescent in situ hybridisation, real-time RT -PCR and immunohistochemistry. We have demonstrated that NT tissues express PPARg both at mRNA and at protein level. PAX8-PPARg fusion gene expression was found in 25% (six of 24) of follicular thyroid carcinomas (FTCs) and in 17% (six of 36) of follicular thyroid adenomas, but in none of the 10 normal tissues, 28 nodular hyperplasias, 38 papillary thyroid carcinomas (PTCs) and 11 poorly differentiated thyroid carcinomas (PDTCs). By real-time RT -PCR, we observed that tumours negative for the PAX8-PPARg rearrangement expressed lower levels of PPARg mRNA than the NT. Overexpression of PPARg transcripts was detected in 80% (four of five) of translocation-positive tumours. Diffuse nuclear staining was significantly (Po0.05) less prevalent in FTCs (53%; 18 of 34), PTCs (49%; 19 of 39) and PDTCs (0%; zero of 13) than in normal tissue (77%; 36 of 47). Peroxisome proliferator-activated receptorg-negative FTCs were more likely to be locally invasive, to persist after surgery, to metastasise and to have poorly differentiated areas. Papillary thyroid carcinomas with a predominantly follicular pattern were more often PPARg negative than classic PTCs (80% vs 28%; P ¼ 0.01). Our results demonstrated that PPARg is underexpressed in translocation-negative thyroid tumours of follicular origin and that a further reduction of PPARg expression is associated with dedifferentiation at later stages of tumour development and progression.

Follicular thyroid carcinoma with an unusual glomeruloid pattern of growth

“…RET/PTC rearrangement detection was investigated with fluorescence in situ hybridization (FISH) using the procedure of Marques et al [5] on isolated nuclei. DNA probe generation from 3 yeast artificial chromosome clones (313F4, 214H10, 344H4) covering the RET locus and probe hybridization were performed as detailed in an earlier report [6] and kindly provided by Professor Horst Zitzelsberger.…”

“…Detection of PAX8-PPARγ rearrangement was investigated with FISH using the procedure of Marques et al [5] on isolated nuclei. BAC probes for PPARγ (RPCI1130 G23, BAC PAC Resources) and PAX8 (RPCI 1165 I12, BAC PAC Resources) were used.…”

Underexpression of PPARγ is associated with aneuploidy and lower differentiation of thyroid tumours of follicular origin

“…In a previous study by our group (22), PPARÁ protein was detected by IHC in 77% of normal thyroid tissues (NTs), 71% of NHs (P>0.05, vs. NT), 62% of FTAs (P>0.05, vs. NT), 53% of FTCs (P=0.03, vs. NT) and 49% of PTCs (P=0.01, vs. NT). All PDTCs/ATC were negative (P<0.0001, vs. normal thyroid tissue).…”

“…PAX8PPARÁ fusion gene was analysed in the entire series by RT-PCR (n=80) or FISH (n=4), and the remaining cases (n=11) by both techniques, as described previously (2,22). All the samples were negative for the PAX8PPARÁ fusion gene.…”

“…In a previous study (22), we demonstrated that follicular carcinomas that do not express PPARÁ protein by immunohistochemistry (IHC) are more prone to develop distant metastases, to invade locally, to present poorly differentiated areas and to persist after surgery. These results suggest an association between underexpression of PPARÁ and a less differentiated phenotype.…”