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Query: UMLS:C0596263 (carcinogenesis)
 64,820 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Peroxisome proliferator-activated receptor gamma (PPAR gamma) is a nuclear receptor involved in such cellular processes as adipogenesis, inflammation, atherosclerosis, cell cycle control, apoptosis, and carcinogenesis. PPAR gamma gene mutations have been found in 4 of 55 sporadic colon cancers, and a chimeric PAX8-PPAR gamma 1 gene frequently generates a chromosomal translocation in thyroid follicular carcinomas, implicating PPAR gamma in tumor suppression. We investigated whether PPAR gamma is involved in the growth regulation of normal and tumor thyroid cells. We found no mutations in PPAR gamma exons 3 and 5 in human thyroid carcinoma cell lines and tissues. Moreover, 1 cell line (NPA) of 6 analyzed did not express PPAR gamma. Treatment of NPA with PPAR gamma agonists did not induce any inhibitory effect. Conversely, PPAR gamma agonists and PPAR gamma overexpression led to a drastic reduction of the cell growth rate in PPAR gamma-expressing thyroid carcinoma cells. Restoration of PPAR gamma expression in NPA cells induced cell growth inhibition; PPAR gamma agonists induced further inhibition. Growth inhibition induced by PPAR gamma agonists or by PPAR gamma gene overexpression in thyroid carcinoma cells was associated with increased p27 protein levels and apoptotic cell death. Should these data be confirmed, PPAR gamma could be a novel target for innovative therapy of thyroid carcinoma, particularly anaplastic carcinomas, which represent one of the most aggressive tumors in mankind and are unresponsive to conventional therapy.
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PMID:Inhibitory effects of peroxisome poliferator-activated receptor gamma on thyroid carcinoma cell growth. 1236 66

Although dietary gamma-linolenic acid (GLA) and its 15-lipoxygenase metabolite, 15S-hydroxyeicosatrienoic acid (15S-HETrE), have been reported to exert antiproliferative activities in other systems, their role in prostatic carcinogenesis is unknown. To evolve a possible mechanism for the suppressive effect on growth of prostatic cells, we incubated GLA and 15S-HETrE with androgen-dependent prostatic adenocarcinoma cells. 15S-HETrE but not GLA markedly inhibited [(3)H]thymidine uptake in parallel with the upregulation of peroxisome proliferator-activated receptor-gamma expression (a growth modulating nuclear receptor). The data, taken together, suggest that dietary GLA via its in vivo metabolite 15S-HETrE could serve as an endogenous adjunct to attenuate prostatic tumorigenesis.
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PMID:Activation of peroxisome proliferator-activated receptor (PPAR)-gamma by 15S-hydroxyeicosatrienoic acid parallels growth suppression of androgen-dependent prostatic adenocarcinoma cells. 1244 73

The molecular genetic basis of thyroid carcinogenesis is not well understood. Most of the existing models of thyroid cancer only rarely show metastases, and this has limited progress in the understanding of the molecular events in thyroid cancer invasion and metastasis. We have recently generated a mutant mouse by introducing a dominant negative mutant thyroid hormone nuclear receptor gene, TRbetaPV, into the TRbeta gene locus. In this TRbetaPV mouse, the regulation of the thyroid-pituitary axis is disrupted, leading to a mouse with high levels of circulating thyroid-stimulating hormone and extensive hyperplasia of follicular epithelium within the thyroid. As TRbeta(PV/PV) mice, but not TRbeta(PV/+) mice, aged, metastatic thyroid carcinoma developed. Histologic evaluation of thyroids of 5-14-month-old mice showed capsular invasion (91%), vascular invasion (74%), anaplasia (35%), and metastasis to the lung and heart (30%). Previous models of thyroid cancer have focused on genes that control initial carcinogenesis, but this model provides an unusual opportunity to study the alterations in gene regulation that occur with clinically relevant changes during progression and metastasis in a predictable fashion.
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PMID:Mice with a mutation in the thyroid hormone receptor beta gene spontaneously develop thyroid carcinoma: a mouse model of thyroid carcinogenesis. 1249 73

The induction of P450 4A enzymes by peroxisome proliferators (PPs) and fatty acids is mediated by the peroxisome proliferator activated receptor alpha (PPAR alpha) that binds to response elements in target genes as a heterodimer with the retinoid X receptor (RXR). The consensus sequence recognized by PPAR/RXR heterodimers, contains an imperfect direct repeat of two nuclear receptor binding motifs separated by a single nucleotide. This repeat is preceded by a conserved A/T rich sequence that is required for function. In mice, chronic exposure to PPs results in PPAR alpha mediated liver hypertrophy, hyperplasia and carcinogenesis accompanied by a proliferation of peroxisomes. In contrast, humans exhibit a reduced sensitivity to PP pathogenesis. This could reflect >10-fold lower PPAR alpha levels relative to mice as well as differences in targeted genes. In order to identify PPAR responsive human genes, the human hepatoma cell line, HepG2, was engineered to express increased levels of PPAR alpha. Several genes encoding rate-limiting enzymes and branch points in ketone body formation are regulated by PPAR alpha in these cells. In contrast, significant induction by PP is not evident for peroxisomal fatty acid oxidation that is associated with peroxisome proliferation in mice. Human P450 4A11 is not expressed in dividing cultures of cells with enhanced PPAR alpha levels, but it is expressed in confluent cultures expressing elevated amounts of PPAR alpha.
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PMID:Regulation of P450 4A expression by peroxisome proliferator activated receptors. 1250 11

Chromosomal translocations encoding fusion oncoproteins are common in hematological malignancies, sarcomas, and papillary thyroid carcinomas. A recent study of follicular thyroid carcinomas reported a novel chromosomal translocation, t(2;3)(q13;p25), that fused the thyroid-specific transcription factor PAX8 with a nuclear receptor, peroxisome proliferator-activated receptor gamma (PPAR gamma). Herein we report the detection of this putative oncoprotein in 6 of 17 (35%) follicular thyroid carcinomas as well as in 6 of 11 (55%) follicular thyroid adenomas. Concordant expression of protein was found in 91% of those tumors in which PAX8-PPAR gamma mRNA was detected by RT-PCR, whereas a further 20% of follicular tumors were positive for PPAR gamma immunohistochemistry alone. Our findings suggest that the PAX8-PPAR gamma fusion protein promotes differentiated follicular thyroid neoplasia, although it is not sufficient per se for carcinogenesis.
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PMID:Detection of the PAX8-PPAR gamma fusion oncogene in both follicular thyroid carcinomas and adenomas. 1251 76

Peroxisome proliferator activated receptors (PPARs) are members of the nuclear receptor superfamily and are intimately involved in lipid metabolism and energy homeostasis. Activation of these receptors in rodents can lead to hepatomegaly and ultimately hepatic carcinogenesis although the mechanisms by which these processes occur are poorly understood. To further our understanding of these processes and to discriminate between different PPAR mediated signalling pathways, a proteomic approach has been undertaken to identify changes in protein expression patterns in Sprague Dawley rat liver following dosing with a PPARalpha agonist (Wyeth 14643), a PPARgamma agonist (Troglitazone) and a compound with mixed PPARalpha/gamma agonist activity (SB-219994). Using one-and-two-dimensional electrophoresis of tissue lysates a diverse range of protein abundance changes was observed in these tissues. Whilst a number of these proteins have PPAR response elements (PPREs) in their respective promoters, another group was detected whose expression has been documented to be sensitive to peroxisome proliferator administration. Most notably within these groups, proteins involved in lipid catabolism displayed increased expression following drug administration. A further subset of proteins, with less obvious biological implications, also showed altered expression patterns. Where available, sequences upstream of the coding regions of genes not previously known to have PPREs were searched with positional consensus matrices for the presence of PPREs in an attempt to validate these changes. Using such an approach putative PPARgamma and PPARdelta response elements were discovered upstream of the tubulin beta coding region. There was limited overlap in observed protein abundance changes between the three groups, and where this was the case (cytosolic epoxide hydrolase, peroxisomal bifunctional enzyme, hydroxymethyl glutaryl CoA, synthase, long chain acyl-CoA thioesterase), expression of these proteins had previously been shown to be under the control of PPAR activity.
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PMID:Protein expression changes in the Sprague Dawley rat liver proteome following administration of peroxisome proliferator activated receptor alpha and gamma ligands. 1268 17

Peroxisome proliferators comprise a heterogeneous group of compounds known for their ability to cause massive proliferation of peroxisomes and liver carcinogenesis in rodents. In recent years it has become evident that other animals may be threatened by peroxisome proliferators, in particular aquatic organisms living in coastal and estuarine areas. These animals are exposed to a variety of pollutants of industrial, agricultural and urban origin which are potential peroxisome proliferators. Both laboratory and field studies have shown that phthalate ester plasticizers, PAHs and oil derivatives, PCBs, certain pesticides, bleached kraft pulp and paper mill effluents, alkylphenols and estrogens provoke peroxisome proliferation in different fish or bivalve mollusc species. The response appears to be mediated by peroxisome-proliferator activated receptors, members of the nuclear receptor family, recently cloned in fish. Based on these results it is proposed that peroxisome proliferation could be used as a biomarker of exposure to a variety of pollutants in environmental pollution assessment. This is illustrated by a case study in which mussels, used worldwide as sentinels of environmental pollution, were transplanted from reference to contaminated areas and vice versa. In mussels native to an area polluted with PAHs and PCBs, peroxisomal acyl-CoA oxidase (AOX) activity and peroxisomal volume density were 2-3 fold and 5-fold higher, respectively, compared to the reference site. When animals were transplanted to the polluted station, with increased concentration of organic xenobiotics, a concomitant significant increase of AOX was recorded. Conversely, in animals transplanted to the cleaner station, AOX activity and peroxisomal volume density decreased significantly. These results indicate that peroxisome proliferation is a rapid (i.e., two days) and reversible response to pollution in mussels. Before peroxisome proliferation can be implemented as a biomarker in biomonitoring programs, a well-defined protocol should be established and validated in intercalibration and quality assurance programmes. Furthermore, the influence of biotic and abiotic factors, some of which are known to affect peroxisome proliferation (season, tide level, interpopulation and interindividual variability), should be taken into consideration. The possible hepatocarcinogenic effects as well as the potential adverse effects on reproduction, development, and growth of peroxisome proliferators are unknown in aquatic organisms, thus providing a challenge for future investigations.
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PMID:Peroxisome proliferation as a biomarker in environmental pollution assessment. 1274 Aug 26

Multiple promoters and differential splicing of 5' upstream exons are often found in various nuclear receptor genes including steroid receptors. Three promoters control the expression of human estrogen receptor alpha (ERalpha) isoforms: ERalpha-A, ERalpha-B, and ERalpha-C, and two promoters control the expression of human progesterone receptor (PR) isoforms: PR-A and PR-B. The expression levels of these isoforms differ with respect to each other in certain target tissues. The role of these isoforms may differ in various types of cells and tissues. The ER and PR contain CpG islands in the 5' upstream regions. One possible mechanism for changing the transcriptional status is methylation of CpG-enriched regions in these isoforms. We have investigated the expression and methylation status of the three different ERalpha promoters and the two different PR gene promoters by using methylation specific PCR (MSP) and direct DNA sequencing in several endometrial and prostate cancer cell lines and tissues. The results of these experiments suggest that ERalpha-A, ERalpha-B, and PR-A were expressed and ERalpha-C and PR-B were inactivated in endometrial cancers. To the contrary, ERalpha-A and ERalpha-B were inactivated and ERalpha-C, PR-A and PR-B were expressed in all prostate cancer. Treatment with demethylating agent (5-aza-2'-deoxycytidine) restored these gene expressions, suggesting that inactivation of this gene is through methylation. Our MSP and direct DNA sequencing showed that ERalpha-A, ERalpha-B, and PR-A genes were unmethylated and ERalpha-C and PR-B were methylated in endometrial cancers although ERalpha-A and ERalpha-B were methylated and ERalpha-C, PRA and PRB were unmethylated in prostate cancers. These reports clearly demonstrate that selective hypermethylation can selectively silence multiple promoters of steroid receptors in carcinogenesis.
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PMID:Hypermethylation can selectively silence multiple promoters of steroid receptors in cancers. 1277 Jul 52

Invasive cytotrophoblasts play a key role in the development of human placenta and is therefore essential for subsequent development of the embryo. Human implantation is characterized by a major trophoblastic invasion that offers a unique model of a controlled and oriented tumor-like process. The ligand-activated nuclear receptor peroxisome proliferator-activated receptor gamma (PPARgamma) modulates cell growth and differentiation and might be therefore considered as a tumor suppressor. We have recently reported that PPARgamma, in synergy with its dimerization partner retinoid X receptor (RXR)alpha, controls the invasion of human primary cytotrophoblasts. Because these cells are unable to replicate in culture, we have, in the present study, transformed these primary cells with the simian virus 40 large T antigen for studying the role of PPARgamma in cell invasion process. Our results show that the cell line human invasive proliferative extravillous cytotrophoblast (HIPEC) 65 expressed markers of human invasive primary cytotrophoblast as determined by immunocytochemistry, immunobloting and real-time RT-PCR, and were highly invasive in vitro. We have next studied the role of PPARgamma/RXRalpha heterodimers in cell proliferation and invasion. Our results show that PPARgamma and RXRalpha are co-expressed by HIPEC 65 and that, as commonly observed, activation of PPARgamma/RXRalpha heterodimers with the specific PPARgamma agonist rosiglitazone induced lipid droplet accumulation as revealed by oil red O staining. Treatment with rosiglitazone or with the natural PPARgamma agonist 15-deoxy-delta-(12,14) PGJ2 did not modify cell growth, but interestingly, activation of PPARgamma by this synthetic (rosiglitazone) or natural (15d-PGJ2) ligand markedly inhibited cell invasion in a concentration-dependent manner. Finally, we showed that other potential natural PPARgamma ligand such as oxidized-but not native-low-density lipoprotein inhibited cell invasion. This proliferative and invasive human cytotrophoblast cell line from extravillous origin provides a new tool for studying specifically the role of PPARgamma in the control of cell invasion.
Carcinogenesis 2003 Aug
PMID:Human invasive trophoblasts transformed with simian virus 40 provide a new tool to study the role of PPARgamma in cell invasion process. 1280 21

The nuclear receptor Constitutive Androstane Receptor (CAR) binds DNA as a heterodimer with the retinoic-X receptor and activates gene transcription. Previously, in vitro studies have shown that the testosterone metabolites, androstenol and androstenol, inhibit the constitutive transcriptional activity of CAR, suggesting that differences might exist in the response to CAR-mediated gene activation between different sexes. In this study, we have analyzed the response of female and male CD-1 mice to stimulation of hepatocyte proliferation caused by the CAR ligand TCPOBOP. Results showed that the labelling index of female hepatocytes at 24, 30 and 36 h after treatment was much higher than that found in males. The higher proliferative activity of female hepatocytes was associated with increased hepatic levels of cyclin D1, cyclin A, E2F and enhanced phosphorylation of pRb and p107. The increased mitogenic response of females was associated with higher mRNA levels of CYP2B10, a known target of CAR. Administration of androstenol to TCPOBOP-treated mice caused a reduction of labelling index, which was accompanied by a decrease of CYP2B10 and CAR mRNA levels. In conclusion, the results show that, in addition to microsomal detoxification, another biological response elicited by the CAR ligand TCPOBOP, namely, hepatocyte proliferation, occurs at higher levels in female than male mice, suggesting that CAR transcriptional activity in males is partially counteracted by physiological higher levels of testosterone metabolites such as androstenol and androstenol.
Carcinogenesis 2003 Jun
PMID:Sex difference in the proliferative response of mouse hepatocytes to treatment with the CAR ligand, TCPOBOP. 1280 59


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