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

The role of peroxisome-proliferator activated receptor (PPAR)gamma in tumor growth inhibition has been extensively studied during last seven years but still remains debated. Many in vitro and xenograft studies have demonstrated that PPARgamma ligands are anti-tumorigenic due to anti-proliferative, pro-differentiation and anti-angiogenic effects. In animal models, PPARgamma ligands have shown preventive effects against chemical carcinogenesis. On the other hand, evidences are accumulating against the possible use of this ligand activated nuclear receptor in molecular targeting for cancer therapy. The growth inhibitory effects of certain PPARgamma ligands have recently been shown to be independent of PPARgamma-activation. Studies have also come up with results indicating the growth promoting effects of PPARgamma-activation, particularly in certain animal models genetically predisposed to cancer development. Loss-of-function mutations of PPARgamma in tumors and increased susceptibility of PPARgamma heterozygote knockout mice to carcinogenesis suggested a tumor-suppressing role of PPARgamma. However, recent findings do not support PPARgamma as a tumor suppressor gene. Although initial clinical trials with PPARgamma ligand troglitazone reported promising results in liposarcoma and prostate cancers, recent studies failed to show the expected therapeutic values in advanced colorectal and breast cancers. In this review, we have addressed these controversies on potential use of PPARgamma ligands in cancer therapy.
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PMID:Can PPAR gamma ligands be used in cancer therapy? 1557 13

Peroxisome proliferator-activated receptor delta (PPARdelta) is ligand-activated transcription factor of the nuclear receptor superfamily which is recently implicated in carcinogenesis. We examined the expression profiles of PPARdelta in human gastric cancer, normal gastric mucosa and gastric cancer cell lines by RT-PCR, Western blot and immunohistochemistry. PPARdelta mRNA and protein was found to be ubiquitously expressed in all 5 gastric cancer cell lines, 40 gastric cancer samples and 10 normal gastric mucosa from non-cancer patients. Positive immunoreactivity was detected in the nuclei of normal and malignant gastric epithelium. Treatment of gastric cell line MKN45 that overexpressed cyclooxygenase-2 (COX-2) with specific COX-2 inhibitor NS398 resulted in a time- and dose-dependent suppression of PPARdelta expression. In contrast, there was no suppression of PPARdelta in MKN28 gastric cell line with low COX-2 expression. Our results demonstrated the ubiquitous expression of PPARdelta in normal and cancer gastric epithelium. Suppression of PPARdelta may be one of the mechanisms underlying the chemopreventive effects of COX-2 inhibitor.
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PMID:Expression of peroxisome proliferator-activated receptor delta in human gastric cancer and its response to specific COX-2 inhibitor. 1589 Feb 32

Nitric oxide donating aspirin (NO-ASA), consisting of a traditional ASA to which a NO-releasing moiety is covalently attached, is a promising chemopreventive agent against colon cancer. Its mechanism of action is not fully delineated. Here we examined its effect on the expression of the nuclear receptor PPARdelta, whose role in colon carcinogenesis remains highly controversial. We studied histochemically the effect of the meta and para positional isomers of NO-ASA on PPARdelta expression in Min (multiple intestinal neoplasia) and wild-type mice, and on cell proliferation and apoptosis. PPARdelta, minimally expressed in wild-type mice, was significantly expressed in Min mice. para NO-ASA inhibited intestinal tumor incidence (59%) and PPARdelta expression (55.3%) more than meta NO-ASA (38 and 41.5%, respectively). Neither isomer affected cell proliferation, but both induced apoptosis in Min mice (para 52.5% for normal mucosa and 70.3% for tumors; meta 31.4 and 21.9%, respectively). The changes in PPARdelta expression correlated significantly with changes in apoptosis. Furthermore, NO-ASA induced areas of necrosis in intestinal tumors are probably resulting from the induction of atypical apoptosis. Our data suggest that NO-ASA suppresses intestinal tumorigenesis possibly in part through its inhibitory effect on PPARdelta, the expression of which may contribute to intestinal carcinogenesis.
Carcinogenesis 2006 Feb
PMID:NO-donating aspirin isomers downregulate peroxisome proliferator-activated receptor (PPAR)delta expression in APC(min/+) mice proportionally to their tumor inhibitory effect: Implications for the role of PPARdelta in carcinogenesis. 1614 Dec 40

Follicular thyroid carcinomas are associated with a chromosomal translocation that fuses the thyroid-specific transcription factor paired box gene 8 (PAX8) with the nuclear receptor peroxisome proliferator-activated receptor gamma (PPARgamma). This study investigated the transcriptional mechanisms by which PAX8-PPARgamma regulates follicular thyroid cells. In HeLa cells, rat follicular thyroid (FRTL-5) cells, or immortalized human thyroid cells, PAX8-PPARgamma stimulated transcription from PAX8-responsive thyroperoxidase and sodium-iodide symporter promoters in a manner at least comparable with wild-type PAX8. In contrast, PAX8-PPARgamma failed to stimulate transcription from the thyroglobulin promoter and blocked the synergistic stimulation of this promoter by wild-type PAX8 and thyroid transcription factor-1. Unexpectedly, PAX8-PPARgamma transcriptional function on a PPARgamma-responsive promoter was cell-type dependent; in HeLa cells, PAX8-PPARgamma dominantly inhibited expression of the PPARgamma-responsive promoter, whereas in FRTL-5 and immortalized human thyroid cells PAX8-PPARgamma stimulated this promoter. In gel shift analyses, PAX8-PPARgamma bound a PPARgamma-response element suggesting that its transcriptional function is mediated via direct DNA contact. A biological model of PAX8-PPARgamma function in follicular thyroid cells was generated via constitutive expression of the fusion protein in FRTL-5 cells. In this model, PAX8-PPARgamma expression was associated with enhanced growth as assessed by soft agar assays and thymidine uptake. Therefore, PAX8-PPARgamma disrupts normal transcriptional regulation by stimulating some genes and inhibiting others, the net effect of which may mediate follicular thyroid cell growth and loss of differentiation that ultimately leads to carcinogenesis.
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PMID:PAX8-peroxisome proliferator-activated receptor gamma (PPARgamma) disrupts normal PAX8 or PPARgamma transcriptional function and stimulates follicular thyroid cell growth. 1617 7

We have previously published that 2 proven treatments for acute promyelocytic leukemia, As2O3 and retinoic acid, can be antagonistic in vitro. We now report that As2O3 inhibits ligand-induced transcription of the retinoic acid receptor, as well as other nuclear receptors that heterodimerize with the retinoid X receptor alpha (RXRalpha). As2O3 did not inhibit transactivation of the estrogen receptor or the glucocorticoid receptor, which do not heterodimerize with RXRalpha. We further show that As2O3 inhibits expression of several target genes of RXRalpha partners. Phosphorylation of RXRalpha has been reported to inhibit nuclear receptor signaling, and we show by in vivo labeling and phosphoamino acid detection that As2O3 phosphorylated RXRalpha in the N-terminal ABC region exclusively on serine residues. Consistent with our previous data implying a role for JNK in As2O3-induced apoptosis, we show that pharmacologic or genetic inhibition of JNK activation decreased As2O3-induced RXRalpha phosphorylation and blocked the effects of As2O3 on RXRalpha-mediated transcription. A mutational analysis indicated that phosphorylation of a specific serine residue, S32, was primarily responsible for inhibition of RXRalpha-mediated transcription. These data may provide some insight into the rational development of chemotherapeutic combinations involving As2O3 as well as into molecular mechanisms of arsenic-induced carcinogenesis resulting from environmental exposure.
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PMID:Arsenic trioxide inhibits nuclear receptor function via SEK1/JNK-mediated RXRalpha phosphorylation. 1618 97

Thyroid hormone (T3) and peroxisome proliferators have overlapping metabolic effects in the maintenance of lipid homeostasis. Their actions are mediated by their respective receptors: thyroid hormone receptors (TR) and peroxisome proliferator-activated receptors (PPAR). We recently found that a dominantly negative TRbeta mutant (PV) that causes a genetic disease, resistance to thyroid hormone, acts to repress the ligand (troglitazone)-mediated transcriptional activity of PPARgamma in cultured thyroid cells. This finding suggests that TRbeta mutants could crosstalk with PPARgamma-signaling pathways. The present study explored the molecular mechanisms by which PV represses the PPARgamma transcriptional activity. Gel-shift assays show that the PV, similar to wild-type TRbeta, bound to the peroxisome proliferator response element (PPRE) as homodimers and heterodimers with PPARgamma or the retinoid X receptor (RXR), thereby competing with PPARgamma for binding to PPRE and for sequestering RXR. Association of PPRE-bound PV with corepressors [e.g., nuclear receptor corepressor (NCoR)] that led to transcriptional repression was independent of T3 and troglitazone. Chromatin immunoprecipitation assay further demonstrated that, despite the presence of ligands, NCoR was recruited to PPRE-bound PV on a PPARgamma-target gene, the lipoprotein lipase, in vivo, suggesting the dominant action of PV on PPARgamma-mediated transcriptional activity. Thus, the dominant negative action of PV is not limited on the wild-type TRs. The findings that TRbeta mutants affect PPARgamma functions through dominant negative action provide insights into the molecular mechanisms by which TR regulates the PPARgamma-target genes involved in metabolic pathways, lipid homeostasis, and carcinogenesis.
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PMID:Thyroid hormone receptor beta mutants: Dominant negative regulators of peroxisome proliferator-activated receptor gamma action. 1626 Jul 19

Prostate cancer (PC) is one of the main causes of disease and death and represents the second cause of death among men in Brazil. Benign prostate hyperplasia is a progressive and prevalent disease. It is estimated that men present around 50% and 90% of histological evidences of prostate hyperplasia at 50 and 80 years, respectively. While the pathogenesis of prostate neoplasias has been closely related to androgen and their specific nuclear receptor, the molecular mechanisms of cell growth, differentiation and apoptosis processes are still not clearly established. Co-activators and co-repressors could also contribute to prostate carcinogenesis by their binding to nuclear receptors or by interacting with the transcriptional machinery in order to increase the transcription of target genes. AR and type 2 5alpha reductase polymorphisms seem to be associated to the risk for PC. In addition, apoptosis and cellular cycle regulator genes, as well as growth factors, have been reported to be associated with the prostate tumorigenesis. Therefore, changes on the gene expression of normal tissue may be associated to the development of malign phenotype and these genes could be regarded as candidates of prognosis markers. The number of these genes increases every day but the present data needs further studies and correlation with the disease progression.
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PMID:[Molecular biology in the prostate neoplasia]. 1644 63

Peroxisome proliferator-activated receptor (PPAR) gamma is a ligand-activated nuclear receptor that plays a key role in adipogenesis and adipocyte gene expression, and has recently been linked with possible antineoplastic effects in colonic carcinogenesis. PPARgamma2 and gamma3 are two transcripts arising from the PPARgamma gene through differential promoter usage and alternative splicing. We investigated the associations between PPARgamma2 Pro12Ala and PPARgamma3 C-681G gene polymorphisms and colorectal cancer (CRC) risk in a case-control study nested within the Singapore Chinese Health Study. Genotypes for the PPARgamma2 and PPARgamma3 polymorphisms were determined on 362 incident CRC cases and 1164 cohort controls by direct sequencing and by fluorogenic 5'-nuclease assay. Unconditional logistic regression models were used for statistical analyses. With adjustment for CRC risk factors, subjects with one or two copies of the G allele of the PPARgamma2 Pro12Ala polymorphism showed a statistically significant reduction in risk compared to those with the CC genotype [odds ratio (OR)=0.53, 95% confidence interval (CI)=0.30-0.92]. For the PPARgamma3 C-681G polymorphism, subjects with one or two copies of the C allele showed a reduction in risk compared to those with the GG genotype (OR=0.72, 95% CI=0.51-1.04). When PPARgamma2 and PPARgamma3 genotypes were considered simultaneously, the number of putative low-risk genotypes was significantly associated with reduced risk of CRC in a gene-dose-dependent manner; the OR (95% CI) was 0.72 (0.49-1.07) among subjects possessing one low-risk genotype (either PPARgamma2 or PPARgamma3), and the comparable figure among subjects possessing both low-risk genotypes was 0.19 (0.07-0.51).
Carcinogenesis 2006 Sep
PMID:Peroxisome proliferator-activated receptor (PPAR) gamma gene polymorphisms and colorectal cancer risk among Chinese in Singapore. 1651 80

The industrial plasticizer di-(2-ethylhexyl)phthalate (DEHP) is used in manufacturing of a wide variety of polyvinyl chloride (PVC)-containing medical and consumer products. DEHP belongs to a class of chemicals known as peroxisome proliferators (PPs). PPs are a structurally diverse group of compounds that share many (but perhaps not all) biological effects and are characterized as non-genotoxic rodent carcinogens. This review focuses on the effect of DEHP in liver, a primary target organ for the pleiotropic effects of DEHP and other PPs. Specifically, liver parenchymal cells, identified herein as hepatocytes, are a major cell type that are responsive to exposure to PPs, including DEHP; however, other cell types in the liver may also play a role. The PP-induced increase in the number and size of peroxisomes in hepatocytes, so called 'peroxisome proliferation' that results in elevation of fatty acid metabolism, is a hallmark response to these compounds in the liver. A link between peroxisome proliferation and tumor formation has been a predominant, albeit questioned, theory to explain the cause of a hepatocarcinogenic effect of PPs. Other molecular events, such as induction of cell proliferation, decreased apoptosis, oxidative DNA damage, and selective clonal expansion of the initiated cells have been also been proposed to be critically involved in PP-induced carcinogenesis in liver. Considerable differences in the metabolism and molecular changes induced by DEHP in the liver, most predominantly the activation of the nuclear receptor peroxisome proliferator-activated receptor (PPAR)alpha, have been identified between species. Both sexes of rats and mice develop adenomas and carcinomas after prolonged feeding with DEHP; however, limited DEHP-specific human data are available, even though exposure to DEHP and other phthalates is common in the general population. This likely constitutes the largest gap in our knowledge on the potential for DEHP to cause liver cancer in humans. Overall, it is believed that the sequence of key events that are relevant to DEHP-induced liver carcinogenesis in rodents involves the following events whereby the combination of the molecular signals and multiple pathways, rather than a single hallmark event (such as induction of PPARalpha and peroxisomal genes, or cell proliferation) contribute to the formation of tumors: (i) rapid metabolism of the parental compound to primary and secondary bioactive metabolites that are readily absorbed and distributed throughout the body; (ii) receptor-independent activation of hepatic macrophages and production of oxidants; (iii) activation of PPARalpha in hepatocytes and sustained increase in expression of peroxisomal and non-peroxisomal metabolism-related genes; (iv) enlargement of many hepatocellular organelles (peroxisomes, mitochondria, etc.); (v) rapid but transient increase in cell proliferation, and a decrease in apoptosis; (vi) sustained hepatomegaly; (vii) chronic low-level oxidative stress and accumulation of DNA damage; (viii) selective clonal expansion of the initiated cells; (ix) appearance of the pre-neoplastic nodules; (x) development of adenomas and carcinomas.
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PMID:Modes of action and species-specific effects of di-(2-ethylhexyl)phthalate in the liver. 1695 67

1alpha-hydroxyvitamin D(5) [1alpha(OH)D(5)] is an active vitamin D analog showing promising chemopreventive effect in breast carcinogenesis. We previously reported that estrogen receptor (ER)-positive breast cancer cells were sensitive, whereas ER-negative breast cancer cells were relatively resistant to their antiproliferative effects. In the present study, we used ER-negative MDA-MB231, ER-transfected MDA-MB231 (S30) and ER-positive BT474 cell lines to evaluate the possible association between ER status and cellular sensitivity to 1alpha(OH)D(5) treatment. Our results demonstrate that ER expression in ER-negative breast cancer cells (S30) did not increase the sensitivity to 1alpha(OH)D(5), whereas in ER-positive BT474 cells, the significant antiproliferative effect of 1alpha(OH)D(5) was correlated with the downregulation of ER and progesterone receptor expression. Further analysis indicated that both MDA-MB231 and S30 cells express low vitamin D receptor (VDR) at transcriptional level and protein level. However, transfection of VDR failed to restore the sensitivity to 1alpha(OH)D(5) in MDA-MB231 and S30 cells, although VDR direct target gene CYP24 was more responsive to 1alpha(OH)D(5) treatment in MDA-MB231 and S30 cells overexpressing VDR. In addition, nuclear receptor cofactors NCoR1 and SRC1 that could potentially affect VDR action were also low in both MDA-MB231 and S30 cells in comparison with ER-positive, vitamin D-sensitive BT474 cells. These results suggest that in addition to the increased ER and VDR expression, the intact VDR signaling machinery as present in ER-positive, vitamin D-sensitive cells is essential for the antiproliferative action of vitamin D, whereas the direct VDR target genes such as CYP24 can remain responsive to augmented VDR expression.
Carcinogenesis 2007 May
PMID:Overexpression of ER and VDR is not sufficient to make ER-negative MDA-MB231 breast cancer cells responsive to 1alpha-hydroxyvitamin D5. 1713 May 24


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