5468

PPARG

peroxisome proliferator-activated receptor gamma;PPARG;peroxisome proliferator-activated receptor gamma

PPAR-gamma|nuclear receptor subfamily 1 group C member 3|peroxisome proliferator-activated nuclear receptor gamma variant 1

3p25

protein-coding

Peroxisome-proliferator activated receptor-gamma (PPARgamma) belongs to a family of nuclear receptors and acts as receptor for peroxisome-proliferators, steroids, retinoic acids, and polyunsaturated fatty acids. Our study examined the transcript levels of peroxisome-proliferator activated receptor-gamma (PPARgamma) and its co-activator (PGC-1) in a cohort of patients with breast cancer. An invasive breast cancer cell, MDA MB 231 exhibited lower level of expression of PPARgamma, compared to non-invasive MCF-7. Breast cancer tissues (n = 120) exhibited a lower level of PPARgamma mRNA compared to normal tissues (n = 25, p = 0.05). No difference, however, was seen with PGC-1. Although the levels of PPARgamma and PGC-1 did not correlate with nodal involvement and grade, significantly lower levels of PPARgamma were seen in TNM3 and TNM4 tumors and from patients with local recurrence and those who died of breast cancer. Lowest level of PGC-1 was also seen in TNM3 and TNM4 tumors and patients who died of breast cancer. We conclude that there is aberrant expression of PPARgamma and its co-activator, PGC-1, in human breast cancer and low levels of these molecules in cancer tissues are associated with poor clinical outcomes.

BACKGROUND: Peroxisome proliferator-activated receptor gamma (PPARgamma) is a ligand dependent transcription factor involved in various processes, including carcinogenesis. We aimed to investigate any possible association of the PPARgammaPro12Ala (rs1801282) polymorphism with risk of developing gastric cancer (GC). PATIENTS AND METHODS: A hospital based case control study was designed covering 50 patients with GC and 120 healthy controls. The frequencies of PPARgammaPro12Ala (rs1801282) were determined using a polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) assay. RESULTS: The Ala12 allele of the PPARgammaPro12Ala G gene was associated with a 1.95 fold increased risk of GC development (p: 0.022; 95% CI: 1.58-2.40). Subgroup analyses showed that the same allele was also associated with metastasis (p: 0.000; OR:4.09; 95%CI:2.273-7.368) and differentiation (p: 0.004; OR:1.95; 95%CI:1.335-2.875) in patients with GC. CONCLUSION: This study suggests that the PPARgammaPro12Ala G (Ala12) allele might be associated with development, differentiation and metastatic process of GC in the Turkish population. Further studies conducted in larger study groups and in different ethnic populations will be needed to clarify the exact role of the PPARgammaPro12Ala polymorphism in GC.

Epithelial-mesenchymal transition (EMT) was shown to confer tumor cells with abilities essential for metastasis, including migratory phenotype, invasiveness, resistance to apoptosis, evading immune surveillance, and tumor stem cell traits. Therefore, inhibition of EMT can be an important therapeutic strategy to inhibit tumor metastasis. Here, we show that activation of peroxisome proliferator-activated receptor gamma (PPAR-gamma) inhibits transforming growth factor beta (TGF-beta)-induced EMT in lung cancer cells and prevents metastasis by antagonizing Smad3 function. Activation of PPAR-gamma by synthetic ligands (troglitazone and rosiglitazone) or by a constitutively active form of PPAR-gamma prevents TGF-beta-induced loss of E-cadherin expression and inhibits the induction of mesenchymal markers (vimentin, N-cadherin, fibronectin) and matrix metalloproteases. Consistently, activation of PPAR-gamma also inhibited EMT-induced migration and invasion of lung cancer cells. Furthermore, effects of PPAR-gamma ligands were attenuated by siRNA-mediated knockdown of PPAR-gamma, indicating that the ligand-induced responses are PPAR-gamma dependent. Selective knockdown of Smad2 and Smad3 by siRNA showed that TGF-beta-induced EMT is Smad3 dependent in lung cancer cells. Activation of PPAR-gamma inhibits TGF-beta-induced Smad transcriptional activity but had no effect on the phosphorylation or nuclear translocation of Smads. Consistently, PPAR-gamma activation prevented TGF-beta-induced transcriptional repression of E-cadherin promoter and inhibited transcriptional activation of N-cadherin promoter. Finally, treatment of mice with troglitazone or knockdown of Smad3 in tumor cells significantly inhibited TGF-beta-induced experimental metastasis in SCID-Beige mice. Together, with the low toxicity profile of PPAR-gamma ligands, our data show that these ligands may serve as potential therapeutic agents to inhibit metastasis.

AIMS: Follicular thyroid carcinoma (FTC) has been a diagnostic challenge for decades. The PAX8-PPARgamma rearrangement has been detected in FTC and classic papillary thyroid carcinomas (PTCs). The aims of this study were to assess the presence of PAX8-PPARgamma by using tissue microarrays in a large cohort of different thyroid neoplasms, and to assess its diagnostic and prognostic implications. METHODS AND RESULTS: Fluorescence in-situ hybridization (FISH) analysis for PAX8-PPARgamma was performed on 226 thyroid tumours, comprising FTCs (n = 59), PTCs (n = 126), poorly differentiated thyroid carcinomas (PDs; n = 34), follicular thyroid adenomas (FTAs; n = 5), and follicular tumours of unknown malignant potential (FTUMPs; n = 2). PAX8-PPARgamma was detected in 12% of FTCs, 1% of PTCs, 7% of PDs, and in both cases of FTUMP. There was no correlation between the extent of capsular or vascular invasion and PAX8-PPARgamma, or between lymph node or haematogenous metastasis and PAX8-PPARgamma. Overall survival (OS), tumour-specific survival (TSS) and relapse-free-survival (RFS) were not influenced by PAX8-PPARgamma. CONCLUSIONS: In this study, we demonstrate for the first time the presence of PAX8-PPARgamma in PDs and FTUMPs, whereas in FTCs and PTCs the prevalence of PAX8-PPARgamma is lower than previously reported. PAX8-PPARgamma did not correlate with invasiveness or affect prognosis in any tumour type.