PPARG; peroxisome proliferator-activated receptor gamma (3p25)

Gene Summary

Gene:PPARG; peroxisome proliferator-activated receptor gamma
Aliases: GLM1, CIMT1, NR1C3, PPARG1, PPARG2, PPARgamma
Summary:This gene encodes a member of the peroxisome proliferator-activated receptor (PPAR) subfamily of nuclear receptors. PPARs form heterodimers with retinoid X receptors (RXRs) and these heterodimers regulate transcription of various genes. Three subtypes of PPARs are known: PPAR-alpha, PPAR-delta, and PPAR-gamma. The protein encoded by this gene is PPAR-gamma and is a regulator of adipocyte differentiation. Additionally, PPAR-gamma has been implicated in the pathology of numerous diseases including obesity, diabetes, atherosclerosis and cancer. Alternatively spliced transcript variants that encode different isoforms have been described. [provided by RefSeq, Jul 2008]
Databases:OMIM, VEGA, HGNC, Ensembl, GeneCard, Gene
Protein:peroxisome proliferator-activated receptor gamma
Updated:14 December, 2014


What does this gene/protein do?
Show (75)


What pathways are this gene/protein implicaed in?
- Basic mechanism of action of PPARa, PPARb(d) and PPARg and effects on gene expression BIOCARTA
- Nuclear Receptors in Lipid Metabolism and Toxicity BIOCARTA
- Role of PPAR-gamma Coactivators in Obesity and Thermogenesis BIOCARTA
- Visceral Fat Deposits and the Metabolic Syndrome BIOCARTA
- PPAR signaling pathway KEGG
Data from KEGG and BioCarta [BIOCARTA terms] via CGAP

Cancer Overview

Research Indicators

Publications Per Year (1989-2014)
Graph generated 14 December 2014 using data from PubMed using criteria.

Literature Analysis

Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic.

Tag cloud generated 14 December, 2014 using data from PubMed, MeSH and CancerIndex

Notable (6)

Scope includes mutations and abnormal protein expression.

Entity Topic PubMed Papers
Colorectal CancerPPARG and Colorectal Cancer View Publications227
Breast CancerPPARG and Breast Cancer View Publications147
Prostate CancerPPARG and Prostate Cancer View Publications78
Thyroid CancerPAX8-PPARG fusion in Folicular Thyroid Cancer
PAX8-PPARG fusion is present in follicular thyroid cancer (FTC) and follicular variant of papillary thyroid carcinoma (FVPTC), and less frequently in follicular thyroid adenoma (FTA).
View Publications72
Bladder CancerPPARG and Bladder Cancer View Publications42
Stomach CancerPPARG and Stomach Cancer View Publications35

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Related Links

Latest Publications: PPARG (cancer-related)

Giordano TJ, Beaudenon-Huibregtse S, Shinde R, et al.
Molecular testing for oncogenic gene mutations in thyroid lesions: a case-control validation study in 413 postsurgical specimens.
Hum Pathol. 2014; 45(7):1339-47 [PubMed] Related Publications
Molecular testing for oncogenic gene alterations provides clinically actionable information essential for the optimal management of follicular cell thyroid cancer. We aimed to establish the distribution and frequency of common oncogenic gene mutations and chromosomal rearrangements in a comprehensive set of benign and malignant thyroid lesions. A case-control study was conducted in 413 surgical cases comprising 17 distinct histopathologic categories, 244 malignant, 169 benign, and 304 double-blinded specimens. Seventeen alterations of BRAF, HRAS, KRAS, NRAS, PAX8, and RET genes were evaluated using a single validated technology platform. Following verification of analytical sensitivity, accuracy, and precision in model and surgical specimens, 152 molecular positive results were generated in lesions representing multiple stages of progression and epithelial differentiation as well as rare subtypes of primary, secondary, or recurring tumors. Single mutations were found in 58% of primary malignant lesions and 12% of benign (P < .001). In the blinded validation set, mutation distribution and frequency were distinct across variants of follicular and papillary carcinomas. BRAF or RET-PTC was detected exclusively in malignant lesions but not in follicular carcinomas (P < .001). RAS or PAX8-PPARG were present in 23% of adenomas, and NRAS was found in a single nonneoplastic lesion (P = .0014). These data substantiate the diagnostic utility of molecular testing for oncogenic mutations and validate its performance in a variety of surgical specimens. Standardized and validated multianalyte molecular panels can complement the preoperative and postoperative assessment of thyroid nodules and support a growing number of clinical and translational applications with potential diagnostic, prognostic, or theranostic utility.

Related: Thyroid Cancer

Jia Y, Viswakarma N, Reddy JK
Med1 subunit of the mediator complex in nuclear receptor-regulated energy metabolism, liver regeneration, and hepatocarcinogenesis.
Gene Expr. 2014; 16(2):63-75 [PubMed] Free Access to Full Article Related Publications
Several nuclear receptors regulate diverse metabolic functions that impact on critical biological processes, such as development, differentiation, cellular regeneration, and neoplastic conversion. In the liver, some members of the nuclear receptor family, such as peroxisome proliferator-activated receptors (PPARs), constitutive androstane receptor (CAR), farnesoid X receptor (FXR), liver X receptor (LXR), pregnane X receptor (PXR), glucocorticoid receptor (GR), and others, regulate energy homeostasis, the formation and excretion of bile acids, and detoxification of xenobiotics. Excess energy burning resulting from increases in fatty acid oxidation systems in liver generates reactive oxygen species, and the resulting oxidative damage influences liver regeneration and liver tumor development. These nuclear receptors are important sensors of exogenous activators as well as receptor-specific endogenous ligands. In this regard, gene knockout mouse models revealed that some lipid-metabolizing enzymes generate PPARα-activating ligands, while others such as ACOX1 (fatty acyl-CoA oxidase1) inactivate these endogenous PPARα activators. In the absence of ACOX1, the unmetabolized ACOX1 substrates cause sustained activation of PPARα, and the resulting increase in energy burning leads to hepatocarcinogenesis. Ligand-activated nuclear receptors recruit the multisubunit Mediator complex for RNA polymerase II-dependent gene transcription. Evidence indicates that the Med1 subunit of the Mediator is essential for PPARα, PPARγ, CAR, and GR signaling in liver. Med1 null hepatocytes fail to respond to PPARα activators in that these cells do not show induction of peroxisome proliferation and increases in fatty acid oxidation enzymes. Med1-deficient hepatocytes show no increase in cell proliferation and do not give rise to liver tumors. Identification of nuclear receptor-specific coactivators and Mediator subunits should further our understanding of the complexities of metabolic diseases associated with increased energy combustion in liver.

Zurlo D, Assante G, Moricca S, et al.
Cladosporol A, a new peroxisome proliferator-activated receptor γ (PPARγ) ligand, inhibits colorectal cancer cells proliferation through β-catenin/TCF pathway inactivation.
Biochim Biophys Acta. 2014; 1840(7):2361-72 [PubMed] Related Publications
BACKGROUND: Cladosporol A, a secondary metabolite from Cladosporium tenuissimum, exhibits antiproliferative properties in human colorectal cancer cells by modulating the expression of some cell cycle genes (p21(waf1/cip1), cyclin D1).
METHODS: PPARγ activation by cladosporol A was studied by overexpression and RNA interference assays. The interactions between PPARγ and Sp1 were investigated by co-immunoprecipitation and ChIp assays. β-Catenin subcellular distribution and β-catenin/TCF pathway inactivation were analyzed by western blot and RTqPCR, respectively. Cladosporol A-induced β-catenin proteasomal degradation was examined in the presence of the specific inhibitor MG132.
RESULTS: Cladosporol A inhibits cell growth through upregulation of p21(waf1/cip1) gene expression mediated by Sp1-PPARγ interaction. Exposure of HT-29 cells to cladosporol A causes β-catenin nuclear export, proteasome degradation and reduced expression of its target genes. Upon treatment, PPARγ also activates E-cadherin gene at the mRNA and protein levels.
CONCLUSION: In this work we provide evidence that PPARγ mediates the anti-proliferative action of cladosporol A in colorectal cancer cells. Upon ligand activation, PPARγ interacts with Sp1 and stimulates p21(waf1/cip1) gene transcription. PPARγ activation causes degradation of β-catenin and inactivation of the downstream target pathway and, in addition, upregulates E-cadherin expression reinforcing cell-cell interactions and a differentiated phenotype.
GENERAL SIGNIFICANCE: We elucidated the molecular mechanisms by which PPARγ mediates the anticancer activity of cladosporol A.

Related: Colorectal (Bowel) Cancer Signal Transduction CTNNB1 gene

Keller E, Chazenbalk GD, Aguilera P, et al.
Impaired preadipocyte differentiation into adipocytes in subcutaneous abdominal adipose of PCOS-like female rhesus monkeys.
Endocrinology. 2014; 155(7):2696-703 [PubMed] Article available free on PMC after 01/07/2015 Related Publications
Metabolic characteristics of polycystic ovary syndrome women and polycystic ovary syndrome-like, prenatally androgenized (PA) female monkeys worsen with age, with altered adipogenesis of sc abdominal adipose potentially contributing to age-related adverse effects on metabolism. This study examines whether adipocyte morphology and gene expression in sc abdominal adipose differ between late reproductive-aged PA female rhesus monkeys compared with age-matched controls (C). Subcutaneous abdominal adipose of both groups was obtained for histological imaging and mRNA determination of zinc finger protein 423 (Zfp423) as a marker of adipose stem cell commitment to preadipocytes, and CCAAT/enhancer binding protein (C/EBP)α/peroxisome proliferator-activated receptor (PPAR)δ as well as C/EBPα/PPARγ as respective markers of early- and late-stage differentiation of preadipocytes to adipocytes. In all females combined, serum testosterone (T) levels positively correlated with fasting serum levels of total free fatty acid (r(2) = 0.73, P < .002). PA females had a greater population of small adipocytes vs C (P < .001) in the presence of increased Zfp423 (P < .025 vs C females) and decreased C/EBPα (P < .003, vs C females) mRNA expression. Moreover, Zfp423 mRNA expression positively correlated with circulating total free fatty acid levels during iv glucose tolerance testing (P < .004, r(2) = 0.66), whereas C/EBPα mRNA expression negatively correlated with serum T levels (P < .02, r(2) = 0.43). Gene expression of PPARδ and PPARγ were comparable between groups (P = .723 and P = .18, respectively). Early-to-mid gestational T excess in female rhesus monkeys impairs adult preadipocyte differentiation to adipocytes in sc abdominal adipose and may constrain the ability of this adipose depot to safely store fat with age.

Related: PPARD

Koyama N, Nishida Y, Ishii T, et al.
Telmisartan induces growth inhibition, DNA double-strand breaks and apoptosis in human endometrial cancer cells.
PLoS One. 2014; 9(3):e93050 [PubMed] Article available free on PMC after 01/07/2015 Related Publications
Telmisartan, an angiotensin II receptor type 1 blocker, is often used as an antihypertension drug, and it has also been characterized as a peroxisome proliferator-activated receptor-gamma (PPARγ) ligand. The purpose of this study was to elucidate the antitumor effects of telmisartan on endometrial cancer cells. We treated three endometrial cancer cell lines with various concentrations of telmisartan, and we investigated the effects of the telmisartan on the cell proliferation, apoptosis, and their related measurements in vitro. We also administered telmisartan to nude mice with experimental tumors to determine its in vivo effects and toxicity. All three endometrial cancer cell lines were sensitive to the growth-inhibitory effect of telmisartan. The induction of apoptosis was confirmed in concert with the altered expression of genes and proteins related to the apoptosis. We also observed that DNA double-strand breaks (DSBs) were induced in HHUA (human endometrial cancer) cells by telmisartan treatment. In addition, experiments in nude mice showed that telmisartan significantly inhibited human endometrial tumor growth, without toxic side effects. Our results suggest that telmisartan might be a new therapeutic option for the treatment of endometrial cancers.

Related: Apoptosis Endometrial (Uterus) Cancer Endometrial Cancer

Morrison JA, Pike LA, Sams SB, et al.
Thioredoxin interacting protein (TXNIP) is a novel tumor suppressor in thyroid cancer.
Mol Cancer. 2014; 13:62 [PubMed] Article available free on PMC after 01/07/2015 Related Publications
BACKGROUND: Thyroid cancer is the most common endocrine malignancy, and many patients with metastatic differentiated thyroid cancer (DTC), poorly differentiated thyroid cancer (PDTC), and anaplastic thyroid cancer (ATC) fail to respond to conventional therapies, resulting in morbidity and mortality. Additional therapeutic targets and treatment options are needed for these patients. We recently reported that peroxisome proliferator-activated receptor gamma (PPARγ) is highly expressed in ATC and confers an aggressive phenotype when overexpressed in DTC cells.
METHODS: Microarray analysis was used to identify downstream targets of PPARγ in ATC cells. Western blot analysis and immunohistochemistry (IHC) were used to assess thioredoxin interacting protein (TXNIP) expression in thyroid cancer cell lines and primary tumor specimens. Retroviral transduction was used to generate ATC cell lines that overexpress TXNIP, and assays that assess glucose uptake, viable cell proliferation, and invasion were used to characterize the in vitro properties of these cells. An orthotopic thyroid cancer mouse model was used to assess the effect of TXNIP overexpression in ATC cell lines in vivo.
RESULTS: Using microarray analysis, we show that TXNIP is highly upregulated when PPARγ is depleted from ATC cells. Using Western blot analysis and IHC, we show that DTC and ATC cells exhibit differential TXNIP expression patterns. DTC cell lines and patient tumors have high TXNIP expression in contrast to low or absent expression in ATC cell lines and tumors. Overexpression of TXNIP decreases the growth of HTh74 cells compared to vector controls and inhibits glucose uptake in the ATC cell lines HTh74 and T238. Importantly, TXNIP overexpression in T238 cells results in attenuated tumor growth and decreased metastasis in an orthotopic thyroid cancer mouse model.
CONCLUSIONS: Our findings indicate that TXNIP functions as a tumor suppressor in thyroid cells, and its downregulation is likely important in the transition from differentiated to advanced thyroid cancer. These studies underscore the potential of TXNIP as a novel therapeutic target and prognostic indicator in advanced thyroid cancer.

Related: Thyroid Cancer TXNIP

Panza A, Votino C, Gentile A, et al.
Peroxisome proliferator-activated receptor γ-mediated induction of microRNA-145 opposes tumor phenotype in colorectal cancer.
Biochim Biophys Acta. 2014; 1843(6):1225-36 [PubMed] Related Publications
UNLABELLED: MicroRNAs (miRNAs) regulate diverse biological processes by inhibiting translation or inducing degradation of target mRNAs. miR-145 is a candidate tumor suppressor in colorectal carcinoma (CRC). Colorectal carcinogenesis involves deregulation of cellular processes controlled by a number of intertwined chief transcription factors, such as PPARγ and SOX9. Since PPAR family members are able to modulate complex miRNAs networks, we hypothesized a role of miRNA-145 in the interaction between PPARγ and SOX9 in colorectal carcinogenesis. To address this issue, we evaluated gene expression in tissue specimens of CRC patients and we took advantage of invitro models represented by CRC derived cell lines (CaCo2, SW480, HCT116, and HT-29), employing PPARγ activation and/or miRNA-145 ectopic overexpression to analyze how their interplay impact the expression of SOX9 and the development of a malignant phenotype.
RESULTS: PPARγ regulates the expression of miR-145 by directly binding to a PPAR response element (PPRE) in its promoter at -1207/-1194bp from the transcription start site. The binding is essential for miR-145 upregulation by PPARγ upon rosiglitazone treatment. Ectopic expression of miR-145, in turn, regulates SOX9 expression through the binding to specific seed motifs. The PPARγ-miR-145-SOX9 axis overarches cell cycle progression, invasiveness and differentiation of CRC derived cell lines. Together, these results suggest that miR-145 is a novel target of PPARγ, acts as a tumor suppressor in CRC cell lines and is a key regulator of intestinal cell differentiation by directly targeting SOX9, a marker of undifferentiated progenitors in the colonic crypts.

Related: Colorectal (Bowel) Cancer

Papi A, De Carolis S, Bertoni S, et al.
PPARγ and RXR ligands disrupt the inflammatory cross-talk in the hypoxic breast cancer stem cells niche.
J Cell Physiol. 2014; 229(11):1595-606 [PubMed] Related Publications
Cancer stem cells (CSCs) are affected by the local micro-environment, the niche, in which inflammatory stimuli and hypoxia act as steering factors. Here, two nuclear receptors (NRs) agonists, i.e. pioglitazone (PGZ), a ligand of peroxisome proliferator activated receptor-γ, and 6-OH-11-O-hydroxyphenanthrene (IIF), a ligand of retinoid X receptors, were investigated for their capability to interference with the cross-talk between breast CSCs and the niche compartment. We found that IIF potentiates the ability of PGZ to hamper the mammospheres-forming capability of human breast tumours and MCF7 cancer cells, reducing the expression of CSCs regulatory genes (Notch3, Jagged1, SLUG, Interleukin-6, Apolipoprotein E, Hypoxia inducible factor-1α and Carbonic anhydrase IX). Notably, these effects are not observed in normal-MS obtained from human breast tissue. Importantly, NRs agonists abolish the capability of hypoxic MCF7 derived exosomes to induce a pro-inflammatory phenotype in mammary glands fibroblasts. Moreover, NRs agonist also directly acts on breast tumour associated fibroblasts to downregulate nuclear factor-κB pathway and metalloproteinases (MMP2 and MMP9) expression and activity. In conclusion, NRs agonists disrupt the inflammatory cross-talk of the hypoxic breast CSCs niche.

Related: Breast Cancer HIF1A MMP9: matrix metallopeptidase 9

Shashni B, Sharma K, Singh R, et al.
Coffee component hydroxyl hydroquinone (HHQ) as a putative ligand for PPAR gamma and implications in breast cancer.
BMC Genomics. 2013; 14 Suppl 5:S6 [PubMed] Article available free on PMC after 01/07/2015 Related Publications
BACKGROUND: Coffee contains several compounds that have the potential to influence breast cancer risk and survival. However, epidemiologic data on the relation between coffee compounds and breast cancer survival are sparse and inconsistent.
RESULTS: We show that coffee component HHQ has significant apoptotic effect on MDA-MB-231 and MCF-7 cells in vitro, and that ROS generation, change in mitochondrial membrane permeability, upregulation of Bax and Caspase-8 as well as down regulation of PGK1 and PKM2 expression may be important apoptosis-inducing mechanisms. The results suggest that PPARγ ligands may serve as potential therapeutic agents for breast cancer therapy. HHQ was also validated as a ligand for PPARγ by docking procedure.
CONCLUSION: This is the first report on the anti-breast cancer (in vitro) activity of HHQ.

Related: Apoptosis Breast Cancer Signal Transduction

Yang MH, Kim J, Khan IA, et al.
Nonsteroidal anti-inflammatory drug activated gene-1 (NAG-1) modulators from natural products as anti-cancer agents.
Life Sci. 2014; 100(2):75-84 [PubMed] Related Publications
Natural products are rich sources of gene modulators that may be useful in prevention and treatment of cancer. Recently, nonsteroidal anti-inflammatory drug (NSAID) activated gene-1 (NAG-1) has been focused as a target of action against diverse cancers like colorectal, pancreatic, prostate, and breast. A variety of natural agents have been reported to play a pivotal role in regulation of NAG-1 through multiple transcriptional mechanisms. The aim of this paper is to review the NAG-1 modulators derived from natural products including plants, marine organisms, and microorganisms. Plant extracts belonging to the families of Fabaceae (Astragalus membranaceus), Ranunculaceae (Coptis chinensis), Menispermaceae (Coscinium fenestratum), Umbelliferae (Pleurospermum kamtschaticum), Lamiaceae (Marubium vulgare), and Rosaceae (Prunus serotina) increased the protein expression of NAG-1 in human colon cancer or hepatocarcinoma cells. Phytochemicals in the class of flavonoids (apigenin, quercetin, isoliquiritigenin, and 2'-hydroxyflavanone), isoflavonoids (formononetin and genistein), catechins (epigallocatechin gallate and epicatechin gallate), stilbenoids (resveratrol and pinosylvin), phenolics (6-gingerol), phloroglucinols (rottlerin and aspidin PB), terpenoids (18 α-glycyrrhetinic acid, platycodin D, pseudolaric acid B, and xanthorrhizol), alkaloids (berberine, capsaicin, and indole-3-carbinol), lignans (isochaihulactone), anthraquinones (damnacanthal), and allyl sulfides (diallyl disulfide) elicited NAG-1 overexpression in various cancer cells. Pectenotoxin-2 from marine organisms and prodigiosin and anisomycin from microorganisms were also reported as NAG-1 modulators. Several transcription factors including EGR-1, p53, ATF-3, Sp1 and PPARγ were involved in natural products-induced NAG-1 transcriptional signaling pathway.

Related: Cancer Prevention and Risk Reduction

Choi W, Porten S, Kim S, et al.
Identification of distinct basal and luminal subtypes of muscle-invasive bladder cancer with different sensitivities to frontline chemotherapy.
Cancer Cell. 2014; 25(2):152-65 [PubMed] Article available free on PMC after 10/02/2015 Related Publications
Muscle-invasive bladder cancers (MIBCs) are biologically heterogeneous and have widely variable clinical outcomes and responses to conventional chemotherapy. We discovered three molecular subtypes of MIBC that resembled established molecular subtypes of breast cancer. Basal MIBCs shared biomarkers with basal breast cancers and were characterized by p63 activation, squamous differentiation, and more aggressive disease at presentation. Luminal MIBCs contained features of active PPARγ and estrogen receptor transcription and were enriched with activating FGFR3 mutations and potential FGFR inhibitor sensitivity. p53-like MIBCs were consistently resistant to neoadjuvant methotrexate, vinblastine, doxorubicin and cisplatin chemotherapy, and all chemoresistant tumors adopted a p53-like phenotype after therapy. Our observations have important implications for prognostication, the future clinical development of targeted agents, and disease management with conventional chemotherapy.

Related: Basal Cell Carcinoma Cisplatin Doxorubicin Methotrexate TP53 Bladder Cancer Bladder Cancer - Molecular Biology Vinblastine

Caria P, Frau DV, Dettori T, et al.
Optimizing detection of RET and PPARg rearrangements in thyroid neoplastic cells using a home-brew tetracolor probe.
Cancer Cytopathol. 2014; 122(5):377-85 [PubMed] Related Publications
BACKGROUND: Fluorescence in situ hybridization (FISH) to identify specific DNA target sequences in the nuclei of nondividing cells of numerous solid neoplasms has contributed to the introduction of molecular cytogenetics as a useful adjunct to cytology, leading recently to the "marriage" of the 2 disciplines. Numerous cancer molecular markers can now be investigated using different technical approaches, at both the gene and expression levels, in biopsies of various suspected cancers, including differentiated thyroid carcinoma. The limited amount of bioptic material is often insufficient to carry out multiple tests, and optimizing handling of the biopsy is desirable.
METHODS: We have developed a home-brew tetracolor break-apart probe able to simultaneously identify the 2 most common genetic alterations in differentiated thyroid carcinoma: RET/PTC variants in papillary thyroid carcinoma and PAX8/PPARg fusion and variants in follicular thyroid carcinoma.
RESULTS: The probe had 100% specificity, 99.5% sensitivity, and ≥ 3% cutoff. The probe was tested on RET/PTC and PAX8/PPARg RT-PCR positive controls, and feasibility was assessed in 368 thyroid nodule fine-needle aspirations (FNA). In the latter analysis, 24 FNAs had split RET signal, and 9 had split PPARg signal. FISH analysis of available surgically removed nodules confirmed the sensitivity of FISH in detecting abnormal clones and oligoclones.
CONCLUSIONS: The home-brew tetracolor probe showed high feasibility, optimizing the use of the biological material in relation to the available molecular tests and maximizing the FISH experimental and slide-scoring times. This probe may be considered an alternative to RT-PCR when recovery and quality of RNA amplification from FNA are insufficient.

Related: FISH RET Thyroid Cancer

Wang L, Li W, Yang Y, et al.
High expression of sarcoplasmic/endoplasmic reticulum Ca(2+)-ATPase 2b blocks cell differentiation in human liposarcoma cells.
Life Sci. 2014; 99(1-2):37-43 [PubMed] Related Publications
AIMS: We have previously reported that elevated expression of sarcoplasmic/endoplasmic reticulum Ca(2+)-ATPase 2 (SERCA2) was related to the malignant degree of different types of human liposarcoma. Here, we investigated the effects of high SERCA2b expression on proliferation and differentiation of preadipocyte-like human liposarcoma cell line SW872 cells.
MAIN METHODS: SW872 cells were stably transfected with human SERCA2b expressing plasmid. Adipocyte differentiation was assayed by adipogenic gene and protein expression. Cell proliferation, formation of reactive oxygen species (ROS) and phosphorylation of peroxisome proliferator activated receptor gamma (PPAR-γ) and extracellular signal-regulated kinase (ERK) were determined by MTT assay, 2, 7-dichlorofluorescein diacetate (DCF-DA) assay and western blot analysis, respectively.
KEY FINDINGS: High expression of SERCA2b promoted cell proliferation and blocked the differentiation potential of SW872 cells under both in vitro and in vivo differentiation-inducing environment. Moreover, high expression of SERCA2b induced accumulation of ROS and enhanced ERK signaling, thus leading to inactivation of PPAR-γ and down-regulation of adipocyte-specific genes.
SIGNIFICANCE: The results revealed a novel role of SERCA2b in facilitating the blockade of human liposarcoma differentiation, which helps provide a molecular target for therapeutic interventions of human liposarcoma.

Pang X, Shu Y, Niu Z, et al.
PPARγ1 phosphorylation enhances proliferation and drug resistance in human fibrosarcoma cells.
Exp Cell Res. 2014; 322(1):30-8 [PubMed] Related Publications
Post-translational regulation plays a critical role in the control of cell growth and proliferation. The phosphorylation of peroxisome proliferator-activated receptor γ (PPARγ) is the most important post-translational modification. The function of PPARγ phosphorylation has been studied extensively in the past. However, the relationship between phosphorylated PPARγ1 and tumors remains unclear. Here we investigated the role of PPARγ1 phosphorylation in human fibrosarcoma HT1080 cell line. Using the nonphosphorylation (Ser84 to alanine, S84A) and phosphorylation (Ser84 to aspartic acid, S84D) mutant of PPARγ1, the results suggested that phosphorylation attenuated PPARγ1 transcriptional activity. Meanwhile, we demonstrated that phosphorylated PPARγ1 promoted HT1080 cell proliferation and this effect was dependent on the regulation of cell cycle arrest. The mRNA levels of cyclin-dependent kinase inhibitor (CKI) p21(Waf1/Cip1) and p27(Kip1) descended in PPARγ1(S84D) stable HT1080 cell, whereas the expression of p18(INK4C) was not changed. Moreover, compared to the PPARγ1(S84A), PPARγ1(S84D) up-regulated the expression levels of cyclin D1 and cyclin A. Finally, PPARγ1 phosphorylation reduced sensitivity to agonist rosiglitazone and increased resistance to anticancer drug 5-fluorouracil (5-FU) in HT1080 cell. Our findings establish PPARγ1 phosphorylation as a critical event in human fibrosarcoma growth. These findings raise the possibility that chemical compounds that prevent the phosphorylation of PPARγ1 could act as anticancer drugs.

de Biase D, Visani M, Pession A, Tallini G
Molecular diagnosis of carcinomas of the thyroid gland.
Front Biosci (Elite Ed). 2014; 6:1-14 [PubMed] Related Publications
Our understanding of the molecular pathology of thyroid cancer has progressed significantly. It is now apparent that thyroid tumors show a very good correlation between genotype and phenotype, a correlation that is much stronger than that observed in tumors of many other organs. Activation of classic oncogenes (BRAF, RAS, RET) activate MAPK signalling. Other pathways like the PI3K/PTEN/AKT cascade are also active in many thyroid tumors. The analysis of molecular profiles is generating data that can be applied to improve patient management. The common occurrence of thyroid nodules in the general population and the widespread use of fine needle aspiration for the preoperative diagnosis of thyroid nodules creates an unprecedented opportunity to apply what we have learnt from the molecular alterations of thyroid cancer to the clinical arena.

Related: FISH BRAF gene RET Thyroid Cancer KRAS gene PAX8 gene

Rastogi N, Gara RK, Trivedi R, et al.
(6)-Gingerolinduced myeloid leukemia cell death is initiated by reactive oxygen species and activation of miR-27b expression.
Free Radic Biol Med. 2014; 68:288-301 [PubMed] Related Publications
The natural polyphenolic alkanone (6)-gingerol (6G) has established anti-inflammatory and antitumoral properties. However, its precise mechanism of action in myeloid leukemia cells is unclear. In this study, we investigated the effects of 6G on myeloid leukemia cells in vitro and in vivo. The results of this study showed that 6G inhibited proliferation of myeloid leukemia cell lines and primary myeloid leukemia cells while sparing the normal peripheral blood mononuclear cells, in a concentration- and time-dependent manner. Mechanistic studies using U937 and K562 cell lines revealed that 6G treatment induced reactive oxygen species (ROS) generation by inhibiting mitochondrial respiratory complex I (MRC I), which in turn increased the expression of the oxidative stress response-associated microRNA miR-27b and DNA damage. Elevated miR-27b expression inhibited PPARγ, with subsequent inhibition of the inflammatory cytokine gene expression associated with the oncogenic NF-κB pathway, whereas the increased DNA damage led to G2/M cell cycle arrest. The 6G induced effects were abolished in the presence of anti-miR-27b or the ROS scavenger N-acetylcysteine. In addition, the results of the in vivo xenograft experiments in mice indicated that 6G treatment inhibited tumor cell proliferation and induced apoptosis, in agreement with the in vitro studies. Our data provide new evidence that 6G-induced myeloid leukemia cell death is initiated by reactive oxygen species and mediated through an increase in miR-27b expression and DNA damage. The dual induction of increased miR-27b expression and DNA damage-associated cell cycle arrest by 6G may have implications for myeloid leukemia treatment.

Related: Apoptosis

Hahn SS, Tang Q, Zheng F, et al.
Repression of integrin-linked kinase by antidiabetes drugs through cross-talk of PPARγ- and AMPKα-dependent signaling: role of AP-2α and Sp1.
Cell Signal. 2014; 26(3):639-47 [PubMed] Related Publications
Nasopharyngeal carcinoma (NPC) is one of the most common cancers of the head and neck, particularly in Southern China and Southeast Asia with high treatment failure due to the development of local recurrence and distant metastasis. The molecular mechanisms related to the progression of NPC have not been fully understood. In this study, we showed that antidiabetes drugs rosiglitazone and metformin inhibit NPC cell growth through reducing the expression of integrin-linked kinase (ILK). Blockade of PPARγ and AMPKα overcame the effects of rosiglitazone and metformin on ILK protein. Importantly, overexpression of ILK abrogated the effect of rosiglitazone and metformin on NPC cell growth. Furthermore, these agents reduced ILK promoter activity, which was not observed in AP-2α, but not Sp1 site mutation in ILK gene promoter. In addition, silencing of AP-2α or overexpression of Sp1 reversed the effect of these agents on ILK protein expression and cell growth. Chromatin immunoprecipitation (ChIP) assay showed that rosiglitazone induced AP-2α, while metformin reduced Sp1 protein binding to the DNA sequences in the ILK gene promoter. Intriguingly, overexpression of Sp1 abolished the effect of rosiglitazone on AP-2α protein expression. Collectively, we show that rosiglitazone and metformin inhibit ILK gene expression through PPARγ- and AMPKα-dependent signaling pathways that are involved in the regulation of AP-2α and Sp1 protein expressions. The effect of combination of rosiglitazone and metformin demonstrates greater extent than single agent alone. The cross-talk of PPARγ and AMPKα signaling enhances the synergistic effects of rosiglitazone and metformin. This study unveils novel mechanisms by which oral antidiabetes drugs inhibit the growth of human NPC cells.

Related: Nasopharyngeal Cancer Signal Transduction TFAP2A

Wei W, Jiang M, Luo L, et al.
Colorectal cancer susceptibility variants alter risk of breast cancer in a Chinese Han population.
Genet Mol Res. 2013; 12(4):6268-74 [PubMed] Related Publications
Recent genome wide association studies (GWAS) and candidate gene studies have revealed many novel loci associated with colorectal cancer susceptibility. We evaluated the effect of these colorectal cancer-associated variants on the risk of breast cancer in a Chinese Han population. Seven single nucleotide polymorphisms (SNPs) (rs3856806 in PPARG, rs7014346 in POU5F1P1, rs989902 in PTPN13, rs1801278 in IRS1, rs7003146 in TCF7L2, rs1503185 in PTPRJ, and rs63750447 in MLH1) were genotyped in Han Chinese subjects, including 216 patients with breast cancer and 216 matched controls, using the Sequenom MassARRAY platform. The association of genotypes with susceptibility to breast cancer was analyzed using the odds ratio (OR), with 95% confidence interval (CI) and logistic regression. Three SNPs (rs7014346, rs989902, and rs7003146) were found to be significantly associated with the susceptibility of breast cancer. The GA and AA genotypes of rs7003146 in TCF7L2, and the CA and CC genotype of rs989902 in PTPN13 were associated with reduced breast cancer risk in the Chinese Han population based on the best-fit dominant model. The GG genotype of rs7014346 in POU5F1P1 was also significantly associated with decreased breast cancer risk under the best-fit additive model. Our results confirmed the association of rs7014346 in POU5F1P1, rs989902 in PTPN13, and rs7003146 in TCF7L2 with variations in the risk of breast cancer in a Chinese Han population.

Related: Breast Cancer Colorectal (Bowel) Cancer

Leeman-Neill RJ, Kelly LM, Liu P, et al.
ETV6-NTRK3 is a common chromosomal rearrangement in radiation-associated thyroid cancer.
Cancer. 2014; 120(6):799-807 [PubMed] Article available free on PMC after 15/03/2015 Related Publications
BACKGROUND: In their previous analysis of papillary thyroid carcinomas (PTCs) from an Ukrainian-American cohort that was exposed to iodine-131 ((131) I) from the Chernobyl accident, the authors identified RET/PTC rearrangements and other driver mutations in 60% of tumors.
METHODS: In this study, the remaining mutation-negative tumors from that cohort were analyzed using RNA sequencing (RNA-Seq) and reverse transcriptase-polymerase chain reaction to identify novel chromosomal rearrangements and to characterize their relation with radiation dose.
RESULTS: The ETS variant gene 6 (ETV6)-neurotrophin receptor 3 (NTRK3) rearrangement (ETV6-NTRK3) was identified by RNA-Seq in a tumor from a patient who received a high (131) I dose. Overall, the rearrangement was detected in 9 of 62 (14.5%) post-Chernobyl PTCs and in 3 of 151 (2%) sporadic PTCs (P = .019). The most common fusion type was between exon 4 of ETV6 and exon 14 of NTRK3. The prevalence of ETV6-NTRK3 rearrangement in post-Chernobyl PTCs was associated with increasing (131) I dose, albeit at borderline significance (P = .126). The group of rearrangement-positive PTCs (ETV6-NTRK3, RET/PTC, PAX8-PPARγ) was associated with significantly higher dose response compared with the group of PTCs with point mutations (BRAF, RAS; P < .001). In vitro exposure of human thyroid cells to 1 gray of (131) I and γ-radiation resulted in the formation of ETV6-NTRK3 rearrangement at a rate of 7.9 × 10(-6) cells and 3.0 × 10(-6) cells, respectively.
CONCLUSIONS: The authors report the occurrence of ETV6-NTRK3 rearrangements in thyroid cancer and demonstrate that this rearrangement is significantly more common in tumors associated with exposure to (131) I and has a borderline significant dose response. Moreover, ETV6-NTRK3 rearrangement can be directly induced in thyroid cells by ionizing radiation in vitro and, thus, may represent a novel mechanism of radiation-induced carcinogenesis.

Related: NTRK3 gene Thyroid Cancer USA ETV6 (TEL) gene

Tsukahara T, Matsuda Y, Haniu H
PSF knockdown enhances apoptosis via downregulation of LC3B in human colon cancer cells.
Biomed Res Int. 2013; 2013:204973 [PubMed] Article available free on PMC after 15/03/2015 Related Publications
Our previous study demonstrated that PTB-associated splicing factor (PSF) is an important regulator of cell death and plays critical roles in the survival and growth of colon cancer cells. However, the molecular mechanism that activates these downstream signaling events remains unknown. To address this issue, we investigated the effects of PSF knockdown in two different colon cancer cell lines, DLD-1 and HT-29. We found that knockdown of PSF markedly decreased the autophagic molecule LC3B in DLD-1 cells but not in HT-29 cells. Furthermore, DLD-1 cells were more susceptible to PSF knockdown-induced cell growth inhibition and apoptosis than HT-29 cells. This susceptibility is probably a result of LC3B inhibition, given the known relationship between autophagy and apoptosis. C3B is associated with a number of physiological processes, including cell growth and apoptotic cell death. Our results suggest that autophagy is inhibited by PSF knockdown and that apoptosis and cell growth inhibition may act together to mediate the PSF-LC3B signaling pathway. Furthermore, we found that the peroxisome proliferator-activated receptor gamma (PPARγ)-PSF complex induced LC3B downregulation in DLD-1 cells. The results of this study identify a new physiological role for the PSF-LC3B axis as a potential endogenous modulator of colon cancer treatment.

Related: Apoptosis

Xu X, Padilla MT, Li B, et al.
MUC1 in macrophage: contributions to cigarette smoke-induced lung cancer.
Cancer Res. 2014; 74(2):460-70 [PubMed] Article available free on PMC after 15/01/2015 Related Publications
Expression of the pro-oncogenic mucin MUC1 is elevated by inflammation in airway epithelial cells, but the contributions of MUC1 to the development of lung cancer are uncertain. In this study, we developed our finding that cigarette smoke increases Muc1 expression in mouse lung macrophages, where we hypothesized MUC1 may contribute to cigarette smoke-induced transformation of bronchial epithelial cells. In human macrophages, cigarette smoke extract (CSE) strongly induced MUC1 expression through a mechanism involving the nuclear receptor PPAR-γ. CSE-induced extracellular signal-regulated kinase (ERK) activation was also required for MUC1 expression, but it had little effect on MUC1 transcription. RNA interference-mediated attenuation of MUC1 suppressed CSE-induced secretion of TNF-α from macrophages, by suppressing the activity of the TNF-α-converting enzyme (TACE), arguing that MUC1 is required for CSE-induced and TACE-mediated TNF-α secretion. Similarly, MUC1 blockade after CSE induction through suppression of PPAR-γ or ERK inhibited TACE activity and TNF-α secretion. Conditioned media from CSE-treated macrophages induced MUC1 expression and potentiated CSE-induced transformation of human bronchial epithelial cells in a TNF-α-dependent manner. Together, our results identify a signaling pathway involving PPAR-γ, ERK, and MUC1 for TNF-α secretion induced by CSE from macrophages. Furthermore, our results show how MUC1 contributes to smoking-induced lung cancers that are driven by inflammatory signals from macrophages.

Related: Lung Cancer MUC1 gene TNF

Koyama M, Sowa Y, Horinaka M, et al.
Peroxisome proliferator-activated receptor γ ligand troglitazone and TRAIL synergistically induce apoptosis.
Oncol Rep. 2014; 31(2):947-54 [PubMed] Related Publications
Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is known to cause apoptosis in several types of malignant tumor cells through its interaction with the death domain-containing receptor, death receptor 5 (DR5). In the present study, we showed that co-treatment with troglitazone (TGZ), a synthetic ligand of peroxisome proliferator-activated receptor γ (PPARγ), and TRAIL synergistically induced apoptosis through DR5 upregulation in human colon cancer DLD-1 cells. TGZ elevated DR5 expression at the promoter level through the CCAAT/enhancer-binding protein homologous protein (CHOP) binding site. These results suggest that combined treatment with TGZ and TRAIL may be promising as a new therapy against malignant tumors.

Related: Apoptosis DDIT3 gene

Sawayama H, Ishimoto T, Watanabe M, et al.
Small molecule agonists of PPAR-γ exert therapeutic effects in esophageal cancer.
Cancer Res. 2014; 74(2):575-85 [PubMed] Related Publications
The transcription factor PPAR-γ plays various roles in lipid metabolism, inflammation, cellular differentiation, and apoptosis. PPAR-γ agonists used to treat diabetes may have utility in cancer treatment. Efatutazone is a novel later generation PPAR-γ agonist that selectively activates PPAR-γ target genes and has antiproliferative effects in a range of malignancies. In this study, we investigated PPAR-γ status in esophageal squamous cell carcinoma (ESCC) and investigated the antiproliferative effects of efatutazone. PPAR-γ was expressed heterogeneously in ESCC, in which it exhibited an inverse relationship with Ki-67 expression. PPAR-γ expression was associated independently with good prognosis in ESCC. Efatutazone, but not the conventional PPAR-γ agonist troglitazone, inhibited ESCC cell proliferation in vitro and in vivo. Mechanistic investigations suggested that efatutazone acted by upregulating p21Cip1 protein in the nucleus through inactivation of the Akt pathway and dephosphorylation of p21Cip1 at Thr145 without affecting the transcriptional activity of p21Cip1. We also found that treatment with efatutazone led to phosphorylation of the EGF receptor and activation of the mitogen-activated protein kinase (MAPK) pathway. Accordingly, the combination of efatutazone with the antiepithelial growth factor receptor antibody cetuximab synergized to negatively regulate the phosphoinositide 3-kinase-Akt and MAPK pathways. Together, our results suggest that efatutazone, alone or in combination with cetuximab, may offer therapeutic effects in ESCC.

Related: CDKN1A Cancer of the Esophagus Esophageal Cancer Signal Transduction Cetuximab (Erbitux)

Parvaiz F, Manzoor S, Iqbal J, et al.
Hepatitis C virus nonstructural protein 5A favors upregulation of gluconeogenic and lipogenic gene expression leading towards insulin resistance: a metabolic syndrome.
Arch Virol. 2014; 159(5):1017-25 [PubMed] Related Publications
Chronic hepatitis C is a lethal blood-borne infection often associated with a number of pathologies such as insulin resistance and other metabolic abnormalities. Insulin is a key hormone that regulates the expression of metabolic pathways and favors homeostasis. In this study, we demonstrated the molecular mechanism of hepatitis C virus (HCV) nonstructural protein 5A (NS5A)-induced metabolic dysregulation. We showed that transient expression of HCV NS5A in human hepatoma cells increased lipid droplet formation through enhanced lipogenesis. We also showed increased transcriptional expression of peroxisome proliferator-activated receptor gamma coactivator (PGC)-1α and diacylglycerol acyltransferase-1 (DGAT-1) in NS5A-expressing cells. On the other hand, there was significantly reduced transcriptional expression of microsomal triglyceride transfer protein (MTP) and peroxisome proliferator-activated receptor γ (PPARγ) in cells expressing HCV NS5A. Furthermore, increased gluconeogenic gene expression was observed in HCV-NS5A-expressing cells. In addition, it was also shown that HCV-NS5A-expressing hepatoma cells show serine phosphorylation of IRS-1, thereby hampering metabolic activity and contributing to insulin resistance. Therefore, this study reveals that HCV NS5A is involved in enhanced gluconeogenic and lipogenic gene expression, which triggers metabolic abnormality and impairs insulin signaling pathway.

Related: Liver Cancer Signal Transduction

Avasarala S, Bikkavilli RK, Van Scoyk M, et al.
Heterotrimeric G-protein, Gα16, is a critical downstream effector of non-canonical Wnt signaling and a potent inhibitor of transformed cell growth in non small cell lung cancer.
PLoS One. 2013; 8(10):e76895 [PubMed] Article available free on PMC after 15/01/2015 Related Publications
G-protein-coupled receptors (GPCR) are the largest family of cell surface molecules that play important role/s in a number of biological and pathological processes including cancers. Earlier studies have highlighted the importance of Wnt7a signaling via its cognate receptor Frizzled9, a GPCR, in inhibition of cell proliferation, anchorage-independent growth, and reversal of transformed phenotype in non small cell lung cancer primarily through activation of the tumor suppressor, PPARγ. However, the G-protein effectors that couple to this important tumor suppressor pathway have not been identified, and are of potential therapeutic interest. In this study, by using two independent Wnt7a/Frizzled9-specific read-outs, we identify Gα16 as a novel downstream effector of Wnt7a/Frizzled9 signaling. Interestingly, Gα16 expression is severely down-regulated, both at the messenger RNA levels and protein levels, in many non small cell lung cancer cell lines. Additionally, through gene-specific knock-downs and expression of GTPase-deficient forms (Q212L) of Gα16, we also establish Gα16 as a novel regulator of non small cell lung cancer cell proliferation and anchorage-independent cell growth. Taken together, our data not only establish the importance of Gα16 as a critical downstream effector of the non-canonical Wnt signaling pathway but also as a potential therapeutic target for the treatment of non small cell lung cancer.

Related: Non-Small Cell Lung Cancer Lung Cancer

Forootan FS, Forootan SS, Malki MI, et al.
The expression of C-FABP and PPARγ and their prognostic significance in prostate cancer.
Int J Oncol. 2014; 44(1):265-75 [PubMed] Related Publications
The purpose of this study was to test the hypothesis that cooperative interaction between cutaneous fatty acid-binding protein (C-FABP) and peroxisome proliferator-activated receptors (PPAR) promotes the malignant progression of human prostate cancer. The expression of C-FABP, PPARβ/δ and PPARγ was measured by western blot analysis in prostate cell lines and by immunohistochemical staining in tissue sections of benign prostatic hyperplasia (BPH) and prostatic carcinomas. The correlation between the expression of PPARs and C-FABP was assessed. The significance of increased expression of these proteins was analysed with respect to prognosis and compared with those of alternative biomarkers. The expression levels of C-FABP and PPARγ in prostate cancer cell lines and the cytoplasm and nuclei of carcinoma tissues were significantly (Student's t-test, p<0.05) higher compared to those in benign cell lines and BPH tissues. The raised expression level of C-FABP and PPARγ was significantly correlated with the increased combined Gleason scores (GS) of the carcinomas. Enhanced expression of cytoplasmic C-FABP significantly correlated with increased nuclear PPARγ (Student's t-test, p<0.005). While expression of PPARβ/δ in carcinomas did not correlate with patient outcome, the increased levels of both C-FABP and PPARγ were associated with shorter patient survival. Multivariate analysis indicated that C-FABP was independently associated with patient survival, whereas PPARγ was confounded by C-FABP in predicting patient survival. Thus, the increased C-FABP may interact with PPARγ in a coordinated mechanism to facilitate malignant progression in prostatic cancer. Both C-FABP and PPARγ are suitable as prognostic factors to predict the clinical outcome of prostatic cancer patients.

Related: Prostate Cancer

Kim HJ, Moon JH, Kim HM, et al.
The hypolipidemic effect of cilostazol can be mediated by regulation of hepatic low-density lipoprotein receptor-related protein 1 (LRP1) expression.
Metabolism. 2014; 63(1):112-9 [PubMed] Related Publications
OBJECTIVES: Cilostazol, a selective phosphodiesterase 3 (PDE3) inhibitor, is a vasodilator and an anti-thrombotic agent. The mechanism whereby cilostazol reduces plasma triglyceride is not completely understood. Here we investigated the effect of cilostazol on a remnant lipoprotein receptor, low-density lipoprotein receptor-related protein 1 (LRP1), which has been reported to play an essential role in clearance of circulating triglyceride in the liver.
MATERIALS/METHODS: Total cellular expression, and functional and transcriptional regulation of LRP1 were analyzed in human hepatocarcinoma cell lines incubated with cilostazol. Also, C57BL/6 mice were subjected to high-fat diet (60% kcal) and cilostazol (30 mg/kg) treatment for 10 weeks.
RESULTS: Cilostazol increased both mRNA and protein expression of LRP1 in HepG2 and Hep3B cells. In addition, enhanced transcriptional activity of the LRP1 promoter containing a peroxisome proliferator response element (PPRE) was observed after cilostazol exposure. Cilostazol treatment enhanced the uptake of lipidated apoE3, and this effect was abolished when LRP1 was silenced by siRNA knockdown. High-fat diet induced hyperglycemia with high level of plasma triglycerides, and reduced hepatic LRP1 expression in mice. Treatment with cilostazol for the same period of time, however, successfully prevented this down-regulation of LRP1 expression and reduced plasma triglycerides.
CONCLUSION: Taken together, our results demonstrated that cilostazol enhances LRP1 expression in liver by activating PPARγ through the PPRE in the LRP1 promoter. Increased hepatic LRP1 may be essential for the reduction of circulating triglycerides brought about by cilostazol.

Related: Liver Cancer

Ricarte-Filho JC, Li S, Garcia-Rendueles ME, et al.
Identification of kinase fusion oncogenes in post-Chernobyl radiation-induced thyroid cancers.
J Clin Invest. 2013; 123(11):4935-44 [PubMed] Article available free on PMC after 15/01/2015 Related Publications
Exposure to ionizing radiation during childhood markedly increases the risk of developing papillary thyroid cancer. We examined tissues from 26 Ukrainian patients with thyroid cancer who were younger than 10 years of age and living in contaminated areas during the time of the Chernobyl nuclear reactor accident. We identified nonoverlapping somatic driver mutations in all 26 cases through candidate gene assays and next-generation RNA sequencing. We found that 22 tumors harbored fusion oncogenes that arose primarily through intrachromosomal rearrangements. Altogether, 23 of the oncogenic drivers identified in this cohort aberrantly activate MAPK signaling, including the 2 somatic rearrangements resulting in fusion of transcription factor ETS variant 6 (ETV6) with neurotrophic tyrosine kinase receptor, type 3 (NTRK3) and fusion of acylglycerol kinase (AGK) with BRAF. Two other tumors harbored distinct fusions leading to overexpression of the nuclear receptor PPARγ. Fusion oncogenes were less prevalent in tumors from a cohort of children with pediatric thyroid cancers that had not been exposed to radiation but were from the same geographical regions. Radiation-induced thyroid cancers provide a paradigm of tumorigenesis driven by fusion oncogenes that activate MAPK signaling or, less frequently, a PPARγ-driven transcriptional program.

Related: BRAF gene RET NTRK3 gene Thyroid Cancer ETV6 (TEL) gene

Pagnotta SM, Laudanna C, Pancione M, et al.
Ensemble of gene signatures identifies novel biomarkers in colorectal cancer activated through PPARγ and TNFα signaling.
PLoS One. 2013; 8(8):e72638 [PubMed] Article available free on PMC after 15/01/2015 Related Publications
We describe a novel bioinformatic and translational pathology approach, gene Signature Finder Algorithm (gSFA) to identify biomarkers associated with Colorectal Cancer (CRC) survival. Here a robust set of CRC markers is selected by an ensemble method. By using a dataset of 232 gene expression profiles, gSFA discovers 16 highly significant small gene signatures. Analysis of dichotomies generated by the signatures results in a set of 133 samples stably classified in good prognosis group and 56 samples in poor prognosis group, whereas 43 remain unreliably classified. AKAP12, DCBLD2, NT5E and SPON1 are particularly represented in the signatures and selected for validation in vivo on two independent patients cohorts comprising 140 tumor tissues and 60 matched normal tissues. Their expression and regulatory programs are investigated in vitro. We show that the coupled expression of NT5E and DCBLD2 robustly stratifies our patients in two groups (one of which with 100% survival at five years). We show that NT5E is a target of the TNF-α signaling in vitro; the tumor suppressor PPARγ acts as a novel NT5E antagonist that positively and concomitantly regulates DCBLD2 in a cancer cell context-dependent manner.

Related: Colorectal (Bowel) Cancer Signal Transduction TNF

Dozsa A, Dezso B, Toth BI, et al.
PPARγ-mediated and arachidonic acid-dependent signaling is involved in differentiation and lipid production of human sebocytes.
J Invest Dermatol. 2014; 134(4):910-20 [PubMed] Related Publications
The transcriptional basis of sebocyte differentiation and lipid production is mostly unclear. Peroxisome proliferator-activated receptor gamma (PPARγ), a lipid-activated transcription factor, has been implicated in differentiation and lipid metabolism of various cell types. Here, we show that PPARγ is differentially expressed in normal and pathological human sebocytes and appears to have roles in their differentiation and lipid production. We used laser-microdissected normal and pathological human sebaceous glands (SGs) and SZ95 cells (immortalized sebocyte cell line) analyzed by real-time quantitative PCR and immunohistochemistry. Lipids were analyzed by quantitative fluorimetry- and mass spectrometry-based approaches. We have observed that PPARγ and its target genes, ADRP (adipose differentiation-related protein) and PGAR (PPARγ angiopoietin-related protein), are expressed in sebocytes and show association with their level of differentiation. Also, PPARγ is present in normal and hyperplastic SG, whereas its expression levels are decreased in SG adenoma and SG carcinoma cells, reflecting a maturation-linked expression pattern. Furthermore, in SZ95 sebocytes, naturally occurring lipids, including arachidonic acid and arachidonic acid keto-metabolites (e.g., 5-KETE (5-oxo-6E,8Z,11Z,14Z-eicosatetraenoic acid), 12-KETE (12-oxo-5Z,8Z,10E,14Z-eicosatetraenoic acid)), appear to regulate PPARγ signaling pathways, which in turn modulate phospholipid biosynthesis and induce neutral lipid synthesis. Collectively, our findings highlight the importance of endogenous ligand-activated PPARγ signaling in human sebocyte biology and suggest that PPARγ might be a promising candidate for the clinical management of SG disorders.

Related: Signal Transduction


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Cite this page: Cotterill SJ. PPARG gene, Cancer Genetics Web: http://www.cancerindex.org/geneweb/PPARG.htm Accessed: date

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