PPARG | Cancer Genetics Web

Kidney Cancer

Wang Z, Li F, Quan Y, Shen J
Avicularin ameliorates human hepatocellular carcinoma via the regulation of NF‑κB/COX‑2/PPAR‑γ activities.
Mol Med Rep. 2019; 19(6):5417-5423 [PubMed] Free Access to Full Article Related Publications

Hepatocellular carcinoma (HCC) has become a global public health problem. Therefore, the development of novel and effective therapeutic agents for the treatment of HCC is considered an emergency. Avicularin, a bio‑active flavonoid from plants, has been reported to exhibit diverse pharmacological properties. The aim of the present study was to investigate the role of avicularin in HCC and the underlying mechanism of action. Huh7 cells were treated with avicularin in a concentration‑dependent manner, and the cell proliferation was examined using a 3‑(4, 5‑dimethylthiazol‑2‑yl)‑2, 5‑diphenyltetrazolium bromide assay kit. The cell migration and invasion abilities were detected using wounding‑healing assays and Transwell assays. Flow cytometric analysis was performed to investigate the cell cycle distribution and cell apoptosis. The activity of nuclear factor (NF)‑κB (p65), cyclooxygenase‑2 (COX‑2) and peroxisome proliferator‑activated receptor γ (PPAR‑γ) were measured by reverse transcription‑quantitative polymerase chain reaction and western blot analyses, respectively. The results indicated that avicularin treatment markedly decreased cell proliferation concentration‑dependently in HCC, and inhibited cell migration and invasion in Huh7 cells. It was also found that the treatment of avicularin markedly inhibited the G0/G1‑phase cells and decreased the accumulation of S‑phase cells in the cell cycle and induced cell apoptosis. In addition, it was confirmed that the anticancer efficacy of avicularin in HCC was dependent on the regulation of NF‑κB (p65), COX‑2 and PPAR‑γ activities. In conclusion, the findings suggested that avicularin serves an antineoplastic role in HCC and may provide a potential therapeutic strategy for the treatment of HCC.

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Liver Cancer

Tutino V, De Nunzio V, Caruso MG, et al.
Elevated AA/EPA Ratio Represents an Inflammatory Biomarker in Tumor Tissue of Metastatic Colorectal Cancer Patients.
Int J Mol Sci. 2019; 20(8) [PubMed] Free Access to Full Article Related Publications

Chronic inflammation increases the risk of developing certain types of cancer, such as colorectal cancer (CRC). The oxidative metabolism of polyunsaturated fatty acids (PUFAs) has a strong effect on colonic tumorigenesis and the levels of arachidonic acid (AA) and eicosapentaenoic acid (EPA) can contribute to the development of an inflammatory microenvironment. Aim of this study was to evaluate the possible differences in the AA/EPA ratio tissue levels between CRC patients with and without synchronous metastases. Moreover, the expression of the most important inflammatory enzymes and mediators, linked with the AA/EPA ratio, have been also assessed. Sixty-eight patients with CRC were enrolled in the study, of which 33 patients with synchronous metastasis. Fatty acid profile analysis in tissue samples was done to examine the levels of AA and EPA. High levels of the AA/EPA ratio were detected in tumor tissue of patients with metastatic CRC. Moreover, an increase of expression of the main enzymes and mediators involved in inflammation was also detected in the same samples. The lipidomic approach of inflammation allows to evaluate lipid homeostasis changes that occur in cancer and in its metastatic process, in order to identify new biomarkers to be introduced into clinical practice.

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Hao S, Huo S, Du Z, et al.
MicroRNA-related transcription factor regulatory networks in human colorectal cancer.
Medicine (Baltimore). 2019; 98(15):e15158 [PubMed] Free Access to Full Article Related Publications

OBJECTIVE: Colorectal cancer (CRC) is an extremely common gastrointestinal malignancy. The present study aimed to identify microRNAs (miRNAs) and transcription factors (TFs) associated with tumor development.
METHODS: Three miRNA profile datasets were integrated and analyzed to elucidate the potential key candidate miRNAs in CRC. The starBase database was used to identify the potential targets of common differentially expressed miRNAs (DEMs). Transcriptional Regulatory Element Database and Transcriptional Regulatory Relationships Unraveled by Sentence-based Text databases were used to identify cancer-related TFs and the TF-regulated target genes. Functional and pathway enrichment analyses were performed using the Database for Annotation, Visualization and Integration Discovery (DAVID) database, and the miRNA-TF-gene networks were constructed by Cytoscape. Quantitative reverse transcription polymerase chain reaction (qRT-PCR) was used to detect the expression of genes and miRNAs.
RESULTS: In total, 14 DEMs were found in CRC. By bioinformatics analysis, 5 DEMs (miR-145, miR-497, miR-30a, miR-31, and miR-20a) and 8 TFs (ELK4 (ETS-family transcription factor), myeloblastosis proto-oncogene like (MYBL)1, MYBL2, CEBPA, PPARA, PPARD, PPARG, and endothelial PAS domain protein (EPAS1)) appeared to be associated with CRC and were therefore used to construct miRNA-TF-gene networks. From the networks, we found that miR-20a might play the most important role as an miRNA in the networks. By qRT-PCR, we demonstrated that miR-20a was significantly upregulated in CRC tissues. We also performed qRT-PCR to identify the expression of miR-20a-related TFs (PPARA, PPARD, PPARG, EPAS1). Three of them, PPARA, PPARG, and EPAS1, were downregulated in CRC tissues, with statistically significant differences, while the downregulation of PPARD in CRC tissues was not significantly different. Pathway enrichment analyses indicated that the phosphoinositide 3-kinase (PI3K)-Akt signaling pathway was the most significantly enriched pathway. Two main elements of the PI3K-Akt signaling pathway, phosphatase and tensin homolog deleted on chromosome 10 and B-cell lymphoma 2-associated agonist of cell death, were demonstrated to be downregulated in CRC.
CONCLUSION: The present study identified hub miRNAs and miRNA-related TF regulatory networks in CRC, which might be potential targets for the diagnosis and treatment of CRC.

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Bladder Cancer - Molecular Biology

Du Q, Tan Z, Shi F, et al.
PGC1α/CEBPB/CPT1A axis promotes radiation resistance of nasopharyngeal carcinoma through activating fatty acid oxidation.
Cancer Sci. 2019; 110(6):2050-2062 [PubMed] Free Access to Full Article Related Publications

The PPAR coactivator-1α (PGC1α) is an important transcriptional co-activator in control of fatty acid metabolism. Mitochondrial fatty acid oxidation (FAO) is the primary pathway for the degradation of fatty acids and promotes NADPH and ATP production. Our previous study demonstrated that upregulation of carnitine palmitoyl transferase 1 A (CPT1A), the key regulator of FAO, promotes radiation resistance of nasopharyngeal carcinoma (NPC). In this study, we found that high expression of PGC1α is associated with poor overall survival in NPC patients after radiation treatment. Targeting PGC1α could sensitize NPC cells to radiotherapy. Mechanically, PGC1α binds to CCAAT/enhancer binding protein β (CEBPB), a member of the transcription factor family of CEBP, to promote CPT1A transcription, resulting in activation of FAO. Our results revealed that the PGC1α/CEBPB/CPT1A/FAO signaling axis promotes radiation resistance of NPC. These findings indicate that the expression of PGC1α could be a prognostic indicator of NPC, and targeting FAO in NPC with high expression of PGC1α might improve the therapeutic efficacy of radiotherapy.

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Nasopharyngeal Cancer

Pacheco-Velázquez SC, Gallardo-Pérez JC, Díaz D, et al.
Heart myxoma develops oncogenic and metastatic phenotype.
J Cancer Res Clin Oncol. 2019; 145(5):1283-1295 [PubMed] Related Publications

PURPOSE: Heart myxomas have been frequently considered as benign lesions associated with Carney's complex. However, after surgical removal, myxomas re-emerge causing dysfunctional heart.
METHODS: To identify whether cardiac myxomas may develop a metastatic phenotype as occurs in malignant cancers, a profile of several proteins involved in malignancy such as oncogenes (c-MYC, K-RAS and H-RAS), cancer-associated metabolic transcriptional factors (HIF-1α, p53 and PPAR-γ) and epithelial-mesenchymal transition proteins (fibronectin, vimentin, β-catenin, SNAIL and MMP-9) were evaluated in seven samples from a cohort of patients with atrial and ventricular myxomas. The analysis was also performed in: (1) cardiac tissue surrounding the area where myxoma was removed; (2) non-cancer heart tissue (NCHT); and (3) malignant triple negative breast cancer biopsies for comparative purposes.
RESULTS: Statistical analysis applying univariate (Kruskal-Wallis and Dunn's tests) and multivariate analyses (PCA, principal component analysis) revealed that heart myxomas (7-15 times) and myxoma surrounding tissue (22-99 times) vs. NCHT showed high content of c-MYC, p53, vimentin, and HIF-1α, indicating that both myxoma and its surrounding area express oncogenes and malignancy-related proteins as occurs in triple negative breast cancer.
CONCLUSIONS: Based on ROC (receiver operating characteristics) statistical analysis, c-MYC, HIF-1α, p53, and vimentin may be considered potential biomarkers for malignancy detection in myxoma.

Lv S, Wang W, Wang H, et al.
PPARγ activation serves as therapeutic strategy against bladder cancer via inhibiting PI3K-Akt signaling pathway.
BMC Cancer. 2019; 19(1):204 [PubMed] Free Access to Full Article Related Publications

BACKGROUND: Heterogeneity in bladder cancer results in variable clinical outcomes, posing challenges for clinical management of this malignancy. Recent studies suggest both tumor suppressive and oncogenic role of PPARγ in bladder cancer. The fuction of PPARγ signaling pathway in modulating carcinogenesis is controversial.
METHODS: The expression of PPARγ and association with overall survival were analyzed in patients from two cohorts. The effect of PPARγ activation on cell proliferation, cell cycle, and cell apoptosis were determined with the agonists (rosiglitazone and pioglitazone), the inverse agonist (T0070907), and the antagonist (GW9662) in Umuc-3 and 5637 bladder cancer cells. The correlation of PPARγ activation with PI3K-Akt pathway was evaluated with RNA sequencing data from the TCGA cases and 30 human bladder cancer cell lines. The effect of PPARγ activation on tumor growth was validated with subcutaneous tumor models in vivo. The effect of PPARγ activation on PI3K-Akt signaling transduction was determined with multiple assays including immunohistochemistry, flow cytometry, proteomic array, and western blotting.
RESULTS: We showed that PPARγ was a favorable prognostic factor in patients with bladder cancer. PPARγ activation by rosiglitazone and pioglitazone markedly induced cell cycle G2 arrest and apoptosis in bladder cancer cells, which resulted in inhibition of cell proliferation in vitro and suppression of tumor growth in vivo. The underlying mechanism involved marked inhibition of PI3K-Akt pathway.
CONCLUSIONS: This study reported the tumor-suppressive effect of PPARγ agonists in bladder cancer, suggesting that transactivation of PPARγ could be served as a potential strategy for the chemoprevention and therapeutic treatment of bladder cancer.

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Shabani A, Foroozanfard F, Kavossian E, et al.
Effects of melatonin administration on mental health parameters, metabolic and genetic profiles in women with polycystic ovary syndrome: A randomized, double-blind, placebo-controlled trial.
J Affect Disord. 2019; 250:51-56 [PubMed] Related Publications

OBJECTIVE: The aim of this study was to evaluate the effect of melatonin supplementation on mental health parameters, metabolic and genetic parameters in women suffering from polycystic ovary syndrome (PCOS).
METHODS: This randomized, double-blinded, placebo-controlled clinical trial was performed on 58 subjects, aged 18-40 years old. Subjects were randomly allocated to take either 10 mg melatonin (2 melatonin capsules, 5 mg each) (n = 29) or placebo (n = 29) once a day 1 h before bedtime for 12 weeks. Glycemic control and lipid profiles were measured at baseline and after the 12-week intervention. Using RT-PCR method, gene expression related to insulin and lipid metabolism was conducted on peripheral blood mononuclear cells (PBMCs) of PCOS women.
RESULTS: Melatonin supplementation significantly decreased Pittsburgh Sleep Quality Index (β -2.15; 95% CI, -3.62, -0.68; P = 0.005), Beck Depression Inventory index (β -3.62; 95% CI, -5.53, -1.78; P<0.001) and Beck Anxiety Inventory index (β -1.95; 95% CI, -3.41, -0.48; P = 0.01) compared with the placebo. In addition, melatonin administration, compared with the placebo, significantly reduced serum insulin (β -1.20 µIU/mL; 95% CI, -2.14, -0.26; P = 0.01), homeostasis model of assessment-insulin resistance (HOMA-IR) (β -0.28; 95% CI, -0.50, -0.05; P = 0.01), serum total- (β -7.96 mg/dL; 95% CI, -13.75, -2.17; P = 0.008) and LDL-cholesterol levels (β -5.88 mg/dL; 95% CI, -11.42, -0.33; P = 0.03), and significantly increased the quantitative insulin sensitivity check index (QUICKI) (β 0.008; 95% CI, 0.002, 0.014; P = 0.007). Moreover, melatonin supplementation upregulated gene expression of peroxisome proliferator-activated receptor gamma (PPAR-γ) (P = 0.004) and low-density lipoprotein receptor (LDLR) (P = 0.01) compared with the placebo.
CONCLUSIONS: Overall, melatonin administration for 12 weeks had beneficial effects on mental health parameters, insulin levels, HOMA-IR, QUICKI, total- and LDL-cholesterol levels, and gene expression of PPAR-γ and LDLR among women with PCOS.

Karasawa K, Tanigawa K, Harada A, Yamashita A
Transcriptional Regulation of Acyl-CoA:Glycerol-
Int J Mol Sci. 2019; 20(4) [PubMed] Free Access to Full Article Related Publications

Acyl-CoA:glycerol-

Ravi Kiran Ammu VVV, Garikapati KK, Krishnamurthy PT, et al.
Possible role of PPAR-γ and COX-2 receptor modulators in the treatment of Non-Small Cell lung carcinoma.
Med Hypotheses. 2019; 124:98-100 [PubMed] Related Publications

Non-Small Cell lung cancer (NSCLC) accounts for 85% of total lung cancers worldwide, affecting more than 1.5 million people every year. Recent studies reported that lung adenocarcinoma express Peroxisome Proliferator Activated Receptor-γ (PPAR-γ) which is believed to be inactivated due to cytoplasmic accumulation or somatic 'loss of function' of the gene. PPAR-γ reported to play an important role in cell proliferation, cell differentiation and apoptosis via inhibition of NF-kβ pathway. Adenocarcinoma also overexpress cyclooxygenase-2 (COX-2), which is reported to promote angiogenesis and metastasis via TX-A2 production. Therefore, we hypothesize that activation of PPAR-γ (through PPAR-γ agonists) and inhibition of COX-2 (through COX-2 inhibitors) will have beneficial effects in the treatment of NSCLC.

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Non-Small Cell Lung Cancer

Childhood Medulloblastoma / PNET

Lung Cancer

Angiogenesis and Cancer

Hua TNM, Kim MK, Vo VTA, et al.
Inhibition of oncogenic Src induces FABP4-mediated lipolysis via PPARγ activation exerting cancer growth suppression.
EBioMedicine. 2019; 41:134-145 [PubMed] Free Access to Full Article Related Publications

BACKGROUND: c-Src is a driver oncogene well-known for tumorigenic signaling, but little for metabolic function. Previous reports about c-Src regulation of glucose metabolism prompted us to investigate its function in other nutrient modulation, particularly in lipid metabolism.
METHODS: Oil-red O staining, cell growth assay, and tumor volume measurement were performed to determine lipid amount and growth inhibitory effect of treatments in lung cancer cells and xenograft model. Gene expression was evaluated by immunoblotting and relative RT-PCR. Transcriptional activity of peroxisome proliferator-activated receptor gamma (PPARγ) was assessed by luciferase assay. Reactive oxygen species (ROS) was measured using ROS sensing dye. Oxygen consumption rate was evaluated by Seahorse XF Mito Stress Test. Clinical relevance of candidate proteins was examined using patient samples and public database analysis.
FINDINGS: Inhibition of Src induced lipolysis and increased intracellular ROS. Src inhibition derepressed PPARγ transcriptional activity leading to induced expression of lipolytic gene fatty acid binding protein (FABP) 4 which accompanies reduced lipid droplets and decreased tumor growth. The reverse correlation of Src and FABP4 was confirmed in pair-matched lung cancer patient samples, and further analysis using public datasets revealed upregulation of lipolytic genes is associated with better prognosis of cancer patients.
INTERPRETATION: This study provides an insight of how oncogenic factor Src concurrently regulates both cellular signaling pathways and metabolic plasticity to drive cancer progression. FUND: National Research Foundation of Korea and Korea Health Industry Development Institute.

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Lung Cancer

Wang F, Li H, Lou Y, et al.
Insulin‑like growth factor I promotes adipogenesis in hemangioma stem cells from infantile hemangiomas.
Mol Med Rep. 2019; 19(4):2825-2830 [PubMed] Related Publications

Infantile hemangiomas (IH) are the most common infantile neoplasms and are characterized by initial proliferation during infancy and subsequent spontaneous regression within the next 5‑10 years, frequently leaving fibrous fat residues. However, the specific mechanisms underlying the differentiation of hemangioma stem cells (HemSCs) into adipocytes are not clear. The purpose of the present study was to investigate the effect of insulin‑like growth factor I (IGF‑1) on HemSCs from patients with IH and to determine the signaling mechanisms involved. Treatment of HemSCs with IGF‑1 led to upregulation of the protein expression levels of peroxisome proliferator‑activated receptor‑γ (PPARγ). By contrast, inhibition of the IGF‑1 receptor (IGF‑1R) or phosphoinositide 3‑kinase (PI3K) activity decreased the expression of PPARγ, in addition to that of CCAAT/enhancer‑binding protein (C/EBP)α, C/EBPβ, and adiponectin. IGF‑1 upregulated the expression of phosphorylated RAC‑α serine/threonine‑protein kinase in IH cells, whereas a specific PI3K inhibitor or IGF‑1R antibody blocked this effect. These results indicated that IGF‑1 is a pro‑proliferative and pro‑lipogenic factor in IH HemSCs. Taken together, these findings indicated that IGF‑1 is able to upregulate PPARγ by activating the IGF‑1R and PI3K pathways, thereby accelerating lipogenesis and enhancing IH HemSC adipogenesis.

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Soon GST, Chang KTE, Kuick CH, Petersson F
A case of nasal low-grade non-intestinal-type adenocarcinoma with aberrant CDX2 expression and a novel SYN2-PPARG gene fusion in a 13-year-old girl.
Virchows Arch. 2019; 474(5):619-623 [PubMed] Related Publications

We report the first patient (a 13-year-old girl) with a sinonasal low-grade non-intestinal-type adenocarcinoma showing aberrant CDX2 expression both within morular areas and in the tubular component and demonstrate for the first time a SYN2-PPARG gene fusion in this tumor type. The tumor arose from the nasal septum and had not spread beyond the nasal cavity.

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CDX2

Baldan F, Allegri L, Lazarevic M, et al.
Biological and molecular effects of bromodomain and extra-terminal (BET) inhibitors JQ1, IBET-151, and IBET-762 in OSCC cells.
J Oral Pathol Med. 2019; 48(3):214-221 [PubMed] Related Publications

BACKGROUND: Despite improvements in oral squamous cell carcinoma (OSCC) management, survival rates remain relatively low and novel anti-neoplastic agents are needed. Bromodomain and extra-terminal (BET) inhibitors proved to be promising agents for cancer treatment. We investigated the effects of three BET inhibitors (JQ1, IBET-151, IBET-762) on SCC-25 cell line and primary oral cancer cell culture.
METHODS: Cell viability was evaluated by MTT. Protein levels of MCM5 and cleaved-PARP were estimated by Western blot. Clonogenic and migratory abilities were determined by colony forming and scratch assays. BET inhibitors effects on mRNA levels of E-Cadherin, Vimentin, SNAI1, SNAI2, CLU, SERPINI1, MCM5, c-Myc, E2F, IL7R, and PPARg were analyzed by qPCR.
RESULTS: BET inhibitors significantly reduced oral cancer cell viability. JQ1 showed the greatest effect reducing cell viability to 10%, both in SCC-25 and primary OSCC cultures (P < 0.001), compared to control cells. Cells treated with BET inhibitors displayed a reduction to 50% in colony forming capacity compared to control cells (P < 0.0001) and the colonies were smaller; they also had a 50%-60% reduction in migratory capacity (P < 0.05) compared to untreated cells. BET inhibitors had a significant impact on genes related to epithelial to mesenchymal transition and other cancer cell markers, notably on MCM5, a gene related to cell cycle control.
CONCLUSIONS: BET inhibitors induce both OSCC cell death and reduction of tumor aggressiveness. Molecular mechanisms of BET inhibition involve among others, MCM5 downregulation. Importantly, this study demonstrates for the first time the anti-tumoral effect of IBET-151 and IBET-762 in oral cancer.

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Oral Cancer

Oyefiade A, Erdman L, Goldenberg A, et al.
PPAR and GST polymorphisms may predict changes in intellectual functioning in medulloblastoma survivors.
J Neurooncol. 2019; 142(1):39-48 [PubMed] Related Publications

PURPOSE: Advances in the treatment of pediatric medulloblastoma have led to improved survival rates, though treatment-related toxicity leaves children with significant long-term deficits. There is significant variability in the cognitive outcome of medulloblastoma survivors, and it has been suggested that this variability may be attributable to genetic factors. The aim of this study was to explore the contributions of single nucleotide polymorphisms (SNPs) in two genes, peroxisome proliferator activated receptor (PPAR) and glutathione-S-transferase (GST), to changes in general intellectual functioning in medulloblastoma survivors.
METHODS: Patients (n = 44, mean
RESULTS: We identified age at diagnosis, radiation therapy, chemotherapy, and eight SNPs associated with PPARs as predictors of general intellectual functioning. Of the eight SNPs identified, PPARα (rs6008197), PPARγ (rs13306747), and PPARδ (rs3734254) were most significantly associated with long-term changes in general intellectual functioning in medulloblastoma survivors.
CONCLUSIONS: PPAR polymorphisms may predict intellectual outcome changes in children treated for medulloblastoma. Importantly, emerging evidence suggests that PPAR agonists may provide an opportunity to minimize the effects of treatment-related cognitive sequelae in these children.

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Medulloblastoma

Fisch SC, Nikou AF, Wright EA, et al.
Precocious subcutaneous abdominal stem cell development to adipocytes in normal-weight women with polycystic ovary syndrome.
Fertil Steril. 2018; 110(7):1367-1376 [PubMed] Article available free on PMC after 01/12/2019 Related Publications

OBJECTIVE: To examine whether abnormal subcutaneous (SC) abdominal adipose stem cell (ASC) development to adipocytes in polycystic ovary syndrome (PCOS) correlates with hyperandrogenism.
DESIGN: Prospective cohort study.
SETTING: Academic medical center.
PATIENT(S): Eight normal-weight women with PCOS and eight normoandrogenic ovulatory (control) women matched for age and body mass index.
INTERVENTION(S): Circulating hormone and metabolic measurements, intravenous glucose tolerance testing, total body dual-energy X-ray absorptiometry, and SC abdominal fat biopsy.
MAIN OUTCOME MEASURE(S): In vitro ASC commitment to preadipocytes (ZFP423 protein expression, day 0.5), preadipocyte differentiation to adipocytes (PPARγ gene expression, day 3) and adipocyte lipid content (Oil-Red-O fluorescence, day 12) comparisons correlated with clinical outcomes.
RESULT(S): In women with PCOS, SC abdominal ASCs compared with those of control women showed exaggerated commitment to preadipocytes and had greater lipid content in newly formed adipocytes after in vitro maturation. In all women combined, ZFP423 protein expression negatively correlated with fasting plasma glucose levels whereas the lipid content of newly formed adipocytes positively correlated with both PPARγ gene expression and serum free testosterone levels.
CONCLUSION(S): In normal-weight women with PCOS compared with the control group, exaggerated SC abdominal ASC commitment to preadipocytes and enhanced adipocyte lipid content during maturation in vitro negatively and positively correlate with circulating fasting glucose and androgen levels, respectively, as a possible mechanism to maintain glucose-insulin homeostasis when fat accretion is accelerated.

Bajpai M, Seril DN, Van Gurp J, et al.
Effect of Long-Term Mesalamine Therapy on Cancer-Associated Gene Expression in Colonic Mucosa of Patients with Ulcerative Colitis.
Dig Dis Sci. 2019; 64(3):740-750 [PubMed] Related Publications

BACKGROUND: The role of 5-aminosalicylic acid (5-ASA or mesalamine) in the prevention of colorectal cancer in ulcerative colitis (UC) patients was reported, but the effect on molecular targets in UC colon mucosa is unknown.
AIM: This observational study evaluates gene expression levels of 5-ASA targets using serial colon biopsy specimens from UC patients undergoing long-term 5-ASA therapy.
METHODS: Transcript levels were compared between colonoscopic biopsy specimens collected from 62 patients at initial and final follow-up colonoscopy at 2-6 years. All patients had mild-to-moderate UC and were undergoing long-term 5-ASA maintenance. Stepwise multiple linear regression analyses were performed to correlate changes in transcript levels with therapeutic response (Mayo clinical score endoscopy and DAI and/or Nancy histopathology score) and nonclinical variables.
RESULTS: The transcript levels of colorectal carcinogenesis-associated known 5-ASA target genes were significantly reduced after prolonged 5-ASA therapy (P < 0.005-0.03). Multiple linear regression models predicted significant association between transcript levels of Ki-67, NF-kB (p65), PPARγ, COX-2 and IL-8, CDC25A, and CXCL10 with duration of drug (5-ASA) exposure (P ≤ 0.05). Ki-67, NF-kB (p65), and CXCL10 transcripts were also correlated with reduced endoscopy sub-score (P ≤ 0.05). COX-2, IL-8, CDC25A, and TNF transcripts strongly correlated with DAI sub-scores (P ≤ 0.05). Only COX-2 and IL-8 transcript levels correlated (P ≤ 0.05) with Nancy histological score.
CONCLUSION: This study provides molecular evidence of changes in carcinogenesis-related targets/pathways in colon tissue during long-term 5-ASA maintenance therapy that may contribute to the observed chemopreventive effects of 5-ASA in UC patients.

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Heudobler D, Rechenmacher M, Lüke F, et al.
Peroxisome Proliferator-Activated Receptors (PPAR)γ Agonists as Master Modulators of Tumor Tissue.
Int J Mol Sci. 2018; 19(11) [PubMed] Article available free on PMC after 01/12/2019 Related Publications

In most clinical trials, thiazolidinediones do not show any relevant anti-cancer activity when used as mono-therapy. Clinical inefficacy contrasts ambiguous pre-clinical data either favoring anti-tumor activity or tumor promotion. However, if thiazolidinediones are combined with additional regulatory active drugs, so-called 'master modulators' of tumors, i.e., transcriptional modulators, metronomic low-dose chemotherapy, epigenetically modifying agents, protein binding pro-anakoinotic drugs, such as COX-2 inhibitors, IMiDs, etc., the results indicate clinically relevant communicative reprogramming of tumor tissues, i.e., anakoinosis, meaning 'communication' in ancient Greek. The concerted activity of master modulators may multifaceted diversify palliative care or even induce continuous complete remission in refractory metastatic tumor disease and hematologic neoplasia by establishing novel communicative behavior of tumor tissue, the hosting organ, and organism. Re-modulation of gene expression, for example, the up-regulation of tumor suppressor genes, may recover differentiation, apoptosis competence, and leads to cancer control-in contrast to an immediate, 'poisoning' with maximal tolerable doses of targeted/cytotoxic therapies. The key for uncovering the therapeutic potential of Peroxisome proliferator-activated receptor γ (PPARγ) agonists is selecting the appropriate combination of master modulators for inducing anakoinosis: Now, anakoinosis is trend setting by establishing a novel therapeutic pillar while overcoming classic obstacles of targeted therapies, such as therapy resistance and (molecular-)genetic tumor heterogeneity.

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Cancer Prevention and Risk Reduction

Wu Q, Sun S, Li Z, et al.
Tumour-originated exosomal miR-155 triggers cancer-associated cachexia to promote tumour progression.
Mol Cancer. 2018; 17(1):155 [PubMed] Article available free on PMC after 01/12/2019 Related Publications

Emerging evidence supports the pivotal roles of cancer-associated cachexia in breast cancer progression. However, the mediators and mechanisms that mediate cancer-induced cachexia remain unclear. Here, we show that breast cancer-derived exosomes alter adipocytes and muscle cells in terms of increased catabolism characterized by the release of metabolites. Likewise, tumour cells cocultivated with mature adipocytes or C2C12 exhibit an aggressive phenotype through inducing epithelial-mesenchymal transition. Mechanistically, we show that cancer cell-secreted miR-155 promotes beige/brown differentiation and remodel metabolism in resident adipocytes by downregulating the PPARγ expression, but does not significantly affect biological conversion in C2C12. In vitro the use of propranolol ameliorates tumour exosomes-associated cachectic wasting through upregulating the PPARγ expression. These results demonstrate that cancer-derived exosomes reprogram systemic energy metabolism and accelerate cancer-associated cachexia to facilitate tumour progression.

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Breast Cancer

Cancer Prevention and Risk Reduction

Li J, Lu M, Jin J, et al.
miR-449a Suppresses Tamoxifen Resistance in Human Breast Cancer Cells by Targeting ADAM22.
Cell Physiol Biochem. 2018; 50(1):136-149 [PubMed] Related Publications

BACKGROUND/AIMS: Most of estrogen receptor positive breast cancer patients respond well initially to endocrine therapies, but often develop resistance during treatment with selective estrogen receptor modulators (SERMs) such as tamoxifen. Altered expression and functions of microRNAs (miRNAs) have been reportedly associated with tamoxifen resistance. Thus, it is necessary to further elucidate the function and mechanism of miRNAs in tamoxifen resistance.
METHODS: Tamoxifen sensitivity was validated by using Cell Counting Kit-8 in tamoxifen-sensitive breast cancer cells (MCF-7, T47D) and tamoxifen-resistant cells (MCF-7/TAM, T47D/ TAM). Quantitative real-time polymerase chain reaction (qRT-PCR) was performed to detect the expression level of miR-449a in tamoxifen-sensitive/-resistant cells and patient serums. Dual-luciferase assay was used to identify the binding of miR-449a and predicted gene ADAM22. The expression level of ADAM22 was determined by qRT-PCR and western blotting in miR-449a +/- breast cancer cells. Subsequently, rescue experiments were carried out to identify the function of ADAM22 in miR-449a-reduced tamoxifen resistance. Finally, Gene ontology (GO) and Protein-protein interaction analyses were performed to evaluate the potential mechanisms of ADAM22 in regulating tamoxifen resistance.
RESULTS: MiR-449a levels were downregulated significantly in tamoxifen-resistant breast cancer cells when compared with their parental cells, as well as in clinical breast cancer serum samples. Overexpression of miR-449a re-sensitized the tamoxifen-resistant breast cancer cells, while inhibition of miR-449a conferred tamoxifen resistance in parental cells. Luciferase assay identified ADAM22 as a direct target gene of miR-449a. Additionally, silencing of ADAM22 could reverse tamoxifen resistance induced by miR-449a inhibition in ER-positive breast cancer cells. GO analysis results showed ADAM22 was mainly enriched in the biological processes of cell adhesion, cell differentiation, gliogenesis and so on. Protein-protein interaction analyses appeared that ADAM22 might regulate tamoxifen resistance through PPARG, LGI1, KRAS and LYN.
CONCLUSION: Decreased miR-449a causes the upregulation of ADAM22, which induces tamoxifen resistance of breast cancer cells. These results suggest that miR-449a, functioning by targeting ADAM22, contributes to the mechanisms underlying breast cancer endocrine resistance, which may provide a potential therapeutic strategy in ER-positive breast cancers.

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Breast Cancer

Bigoni-Ordóñez GD, Ortiz-Sánchez E, Rosendo-Chalma P, et al.
Molecular iodine inhibits the expression of stemness markers on cancer stem-like cells of established cell lines derived from cervical cancer.
BMC Cancer. 2018; 18(1):928 [PubMed] Article available free on PMC after 01/12/2019 Related Publications

BACKGROUND: Cancer stem cells (CSC) are characterized by deregulated self-renewal, tumorigenicity, metastatic potential, aberrant stemness signaling pathways, resistance to conventional therapy, and the ability to give rise to a progeny of proliferating cells that constitute the bulk of tumors. Targeting CSC will provide novel treatments for cancer. Different investigations have focused on developing complementary approaches that involve natural compounds that decrease chemo-resistance and reduce the side effects of conventional therapies. Since, it has been reported that molecular iodine (I
METHODS: HeLa and SiHa cervical cancer cells were treated with 200uM I
RESULTS: In the present study, monolayer and CSC-enriched cultures (cervospheres) from cervical cancer-derived cell lines, HeLa and SiHa, showed that 200uM I
CONCLUSIONS: All this data led us to suggest a clinical potential use of I

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Cervical Cancer

Fredericks E, Dealtry G, Roux S
Can J Gastroenterol Hepatol. 2018; 2018:4379673 [PubMed] Article available free on PMC after 01/12/2019 Related Publications

Background: The wnt/APC/
Methods: Using qPCR and IHC, we compared

Related:

CTNNB1

Gupta G, Singhvi G, Chellappan DK, et al.
Peroxisome proliferator-activated receptor gamma: promising target in glioblastoma.
Panminerva Med. 2018; 60(3):109-116 [PubMed] Related Publications

Glioblastoma, also known as glioblastoma multiforme, is the most common and worldwide-spread cancer that begins within the brain. Glioblastomas represent 15% of brain tumors. The most common length of survival following diagnosis is 12 to 14 months with less than 3% to 5% of people surviving longer than five years. Without treatment, survival is typically 3 months. Among all receptors, special attention has been focused on the role of peroxisome proliferator-activated receptors (PPARs) in glioblastoma. PPARs are ligand-activated intracellular transcription factors. The PPAR subfamily consists of three subtypes encoded by distinct genes named PPARα, PPARβ/δ, and PPARγ. PPARγ is the most extensively studied subtype of PPAR. There has been interesting preliminary evidence suggesting that diabetic patients receiving PPARγ agonists, a group of anti-diabetics, thiazolidinedione drugs, have an increased median survival for glioblastoma. In this paper, the recent progresses in understanding the potential mechanism of PPARγ in glioblastoma are summarized.

Feng W, Wang C, Liang C, et al.
The Dysregulated Expression of KCNQ1OT1 and Its Interaction with Downstream Factors miR-145/CCNE2 in Breast Cancer Cells.
Cell Physiol Biochem. 2018; 49(2):432-446 [PubMed] Related Publications

BACKGROUND/AIMS: Next-generation sequencing (NGS) has revealed abundant long noncoding RNAs (lncRNAs) that have been characterized as critical components of cancer biology in humans. The present study aims to investigate the role of the lncRNA KCNQ1OT1 in breast cancer (BRCA) as well as the underlying molecular mechanisms and functions of KCNQ1OT1 involved in the progression of BRCA.
METHODS: The Cancer Genome Atlas (TCGA) and StarBase v2.0 were used to obtain the required gene data. Dual luciferase reporter gene assays were conducted to verify the relevant intermolecular target relationships. QRT-PCR and Western blot were performed to measure the expression levels of different molecules. Cell proliferation was detected by using the MTT and colony formation assays, while cell migration and invasion were examined by transwell assay. Variations in cell apoptosis and cell cycle were determined through flow cytometry. A tumor xenograft model was applied to assess tumor growth in vivo.
RESULTS: KCNQ1OT1 was found to be remarkably highly expressed in BRCA tissues and cells. KCNQ1OT1 modulated CCNE2 through sponging miR-145 in BRCA. KCNQ1OT1 promoted tumor growth in vivo by regulating miR-145/CCNE2.
CONCLUSION: The KCNQ1OT1/miR-145/CCNE2 axis plays a critical regulatory role in BRCA, potentially giving rise to BRCA tumorigenesis and progression. These findings provide valuable evidence for improving the diagnosis and treatment of BRCA in the future.

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Breast Cancer

Xiong DD, Qin Y, Xu WQ, et al.
A Network Pharmacology-Based Analysis of Multi-Target, Multi-Pathway, Multi-Compound Treatment for Ovarian Serous Cystadenocarcinoma.
Clin Drug Investig. 2018; 38(10):909-925 [PubMed] Related Publications

BACKGROUND AND OBJECTIVES: Pharmacological control against ovarian serous cystadenocarcinoma has received increasing attention. The purpose of this study was to investigate multi-drug treatments as synergetic therapy for ovarian serous cystadenocarcinoma and to explore their mechanisms of action by the network pharmacology method.
METHODS: Genes acting on ovarian serous cystadenocarcinoma were first collected from GEPIA and DisGeNET. Gene Ontology annotation, Kyoto Encyclopedia of Genes and Genomes pathway, Reactome pathway, and Disease Ontology analyses were then conducted. A connectivity map analysis was employed to identify compounds as treatment options for ovarian serous cystadenocarcinoma. Targets of these compounds were obtained from the Search Tool for Interacting Chemicals (STITCH). The intersections between the ovarian serous cystadenocarcinoma-related genes and the compound targets were identified. Finally, the Kyoto Encyclopedia of Genes and Genomes and Reactome pathways in which the overlapped genes participated were selected, and a correspondence compound-target pathway network was constructed.
RESULTS: A total of 541 ovarian serous cystadenocarcinoma-related genes were identified. The functional enrichment and pathway analyses indicated that these genes were associated with critical tumor-related pathways. Based on the connectivity map analysis, five compounds (resveratrol, MG-132, puromycin, 15-delta prostaglandin J2, and valproic acid) were determined as treatment agents for ovarian serous cystadenocarcinoma. Next, 48 targets of the five compounds were collected. Following mapping of the 48 targets to the 541 ovarian serous cystadenocarcinoma-related genes, we identified six targets (PTGS1, FOS, HMOX1, CASP9, PPARG, and ABCB1) as therapeutic targets for ovarian serous cystadenocarcinoma by the five compounds. By analysis of the compound-target pathway network, we found the synergistic anti-ovarian serous cystadenocarcinoma potential and the underlying mechanisms of action of the five compounds.
CONCLUSION: In summary, latent drugs against ovarian serous cystadenocarcinoma were acquired and their target actions and pathways were determined by the network pharmacology strategy, which provides a new prospect for medicamentous therapy for ovarian serous cystadenocarcinoma. However, further in-depth studies are indispensable to increase the validity of this study.

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Transitional Cell Cancer of the Renal Pelvis and Ureter

Dhawan D, Hahn NM, Ramos-Vara JA, Knapp DW
Naturally-occurring canine invasive urothelial carcinoma harbors luminal and basal transcriptional subtypes found in human muscle invasive bladder cancer.
PLoS Genet. 2018; 14(8):e1007571 [PubMed] Article available free on PMC after 01/12/2019 Related Publications

There is growing evidence that molecular subtypes (e.g. luminal and basal subtypes) affect the prognosis and treatment response in patients with muscle invasive urinary bladder cancer (invasive urothelial carcinoma, iUC). Modeling these subtypes in pre-clinical animal studies is essential, but it is challenging to produce these subtypes, along with other critical host and tumor features, in experimentally-induced animal models. This study was conducted to determine if luminal and basal molecular subtypes are present in naturally-occurring canine iUC, a cancer that mimics the human condition in other key aspects. RNA sequencing was performed on 29 canine treatment naive iUC tissue samples and on four normal canine bladder mucosal samples. Data were aligned to CanFam 3.1, and differentially expressed genes were identified. Unsupervised hierarchical clustering of these genes revealed two distinct groups (n = 13, n = 16). When genes that distinguish basal and luminal subtypes in human cancer (n = 2015) were used to probe genes differentially expressed between normal canine bladder and iUC, 829 enriched signature genes were identified. Unsupervised hierarchical clustering of these genes revealed two distinct groups comprised of 18 luminal subtype tumors and 11 basal subtype tumors. The enriched genes included MMP9, SERPINE2, CAV1, KRT14, and RASA3 in basal tumors, and PPARG, LY6E, CTSE, CDK3, and TBX2 in luminal tumors. In supervised clustering, additional genes of importance in human iUC were identified in canine iUC associated with claudin-low and infiltrated tumors. A smaller panel of genes (n = 60) was identified that distinguished canine luminal and basal iUC with overall 93.1% accuracy. Immune signature patterns similar to those in human iUC were also identified with the greatest enrichment of immune genes being in the basal subtype tumors. These findings provide additional compelling evidence that naturally-occurring canine iUC is a highly relevant and much needed model of human iUC for translational research.

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MMP9: matrix metallopeptidase 9

Bladder Cancer

Bladder Cancer - Molecular Biology

Piragyte I, Clapes T, Polyzou A, et al.
A metabolic interplay coordinated by HLX regulates myeloid differentiation and AML through partly overlapping pathways.
Nat Commun. 2018; 9(1):3090 [PubMed] Article available free on PMC after 01/12/2019 Related Publications

The H2.0-like homeobox transcription factor (HLX) regulates hematopoietic differentiation and is overexpressed in Acute Myeloid Leukemia (AML), but the mechanisms underlying these functions remain unclear. We demonstrate here that HLX overexpression leads to a myeloid differentiation block both in zebrafish and human hematopoietic stem and progenitor cells (HSPCs). We show that HLX overexpression leads to downregulation of genes encoding electron transport chain (ETC) components and upregulation of PPARδ gene expression in zebrafish and human HSPCs. HLX overexpression also results in AMPK activation. Pharmacological modulation of PPARδ signaling relieves the HLX-induced myeloid differentiation block and rescues HSPC loss upon HLX knockdown but it has no effect on AML cell lines. In contrast, AMPK inhibition results in reduced viability of AML cell lines, but minimally affects myeloid progenitors. This newly described role of HLX in regulating the metabolic state of hematopoietic cells may have important therapeutic implications.

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Acute Myeloid Leukemia (AML)

Cancer Prevention and Risk Reduction

Li J, Zhao T, Zhang Y, et al.
Performance evaluation of pathogenicity-computation methods for missense variants.
Nucleic Acids Res. 2018; 46(15):7793-7804 [PubMed] Article available free on PMC after 01/12/2019 Related Publications

With expanding applications of next-generation sequencing in medical genetics, increasing computational methods are being developed to predict the pathogenicity of missense variants. Selecting optimal methods can accelerate the identification of candidate genes. However, the performances of different computational methods under various conditions have not been completely evaluated. Here, we compared 12 performance measures of 23 methods based on three independent benchmark datasets: (i) clinical variants from the ClinVar database related to genetic diseases, (ii) somatic variants from the IARC TP53 and ICGC databases related to human cancers and (iii) experimentally evaluated PPARG variants. Some methods showed different performances under different conditions, suggesting that they were not always applicable for different conditions. Furthermore, the specificities were lower than the sensitivities for most methods (especially, for the experimentally evaluated benchmark datasets), suggesting that more rigorous cutoff values are necessary to distinguish pathogenic variants. Furthermore, REVEL, VEST3 and the combination of both methods (i.e. ReVe) showed the best overall performances with all the benchmark data. Finally, we evaluated the performances of these methods with de novo mutations, finding that ReVe consistently showed the best performance. We have summarized the performances of different methods under various conditions, providing tentative guidance for optimal tool selection.

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TP53

Brandler TC, Liu CZ, Cho M, et al.
Does Noninvasive Follicular Thyroid Neoplasm With Papillary-Like Nuclear Features (NIFTP) Have a Unique Molecular Profile?
Am J Clin Pathol. 2018; 150(5):451-460 [PubMed] Related Publications

Objectives: Recognizing preoperative characteristics of noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) is important for clinical management. Therefore, we assessed presurgical NIFTP molecular profiles using fine-needle aspiration (FNA) material.
Methods: Presurgical FNA reports of 39 surgically confirmed NIFTP cases from January 2013 through May 2017 were assessed for Afirma and ThyroSeq results.
Results: Twenty-one of 39 NIFTP nodules were preoperatively tested with Afirma with two benign and 19 suspicious results. Twenty-seven of 39 nodules were tested with ThyroSeq (nine of 39 had both Afirma and Thyroseq): 18 (67%) had RAS mutations (13 NRAS, four HRAS, one KRAS), and three of 18 had multiple alterations (NRAS + TP53, n = 1; NRAS + PTEN, n = 2). BRAF T599_R603 + EIF1AX mutation (n = 1), PTEN mutation (n = 1), MET overexpression (n = 1), PAX8/PPARG fusion (n = 3), and THADA/IGF2BP3 fusion (n = 3) comprised the remainder.
Conclusions: NIFTP cases most commonly displayed suspicious Afirma results and RAS mutations on ThyroSeq, lacking aggressive/BRAF-V600E-like mutations. While NIFTP remains a surgical entity, the lack of aggressive/BRAF-V600E-like mutations can aid in determining the extent of surgery.

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BRAF

Thyroid Cancer

Miller WA, Wuertz BR, Ondrey FG
PPARγ-Mediated p21 Induction in Aerodigestive Preneoplastic Cell Lines.
Ann Otol Rhinol Laryngol. 2018; 127(10):677-686 [PubMed] Related Publications

INTRODUCTION: Oral leukoplakia is defined as a mucous membrane disorder characterized by white patches that cannot be scraped off. Leukoplakia is the most frequent, potentially premalignant oral mucosa disorder and a good candidate for chemopreventive therapies. Pioglitazone activates peroxisome proliferator-activated receptor gamma (PPARγ), which forms a complex with nuclear cofactors and regulates gene expression of a variety of cell-cycle proteins and is currently being tested preclinically and clinically in aerodigestive cancer prevention.
METHODS: In the present study, we hypothesized that pioglitazone would decrease proliferation of human leukoplakia cells (MSK Leuk1) and transformed bronchial epithelial cells (BEAS-2B) through regulatory changes of G1 checkpoint protein regulators, p21 and cyclin-D1. MSK Leuk1 and BEAS-2B cells were treated with pioglitazone and assayed for cell proliferation and p21 transcriptional activity.
RESULTS: We discovered pioglitazone significantly inhibited cell proliferation in a dose-dependent fashion. We also observed p21 protein induction after treatment with pioglitazone, which was preceded by measurable increases in p21 mRNA induction.
CONCLUSIONS: We conclude the PPARγ activator, pioglitazone, can activate p21, which is associated with decreased proliferation in 2 aerodigestive preneoplastic cell lines. In addition, the p21 gene may be a potential hypothesis-driven biomarker in translational studies of pioglitazone as a chemoprevention agent for aerodigestive cancer.

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