Constitutive expression of PPARγ inhibits proliferation and migration of gastric cancer cells and down-regulates Wnt/β-Catenin signaling pathway downstream target genes TERT and ENAH

Guo, Fang; Ren, Xiyun; Dong, Yingzi; Hu, Xiaomeng; Xu, Dan; Zhou, Haibo; Meng, Fengyan; Zhao, Yong

doi:10.1016/j.gene.2016.03.003

Cited by 33 publications

(23 citation statements)

References 47 publications

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“…The analysis of the expression levels of 7 genes ( WNT1, FZD4, CTNNB1, EP300, CREBBP, TCF7, and MYC ) showed that Pio slightly modulated Wnt pathway in our GSCs and interestingly it did not alter β catenin levels. This finding is in net contrast with previous studies, which reported that Pio was able to decrease expression level of β catenin protein [ 17 , 37 ] or downregulate Wnt/ β catenin signaling pathway downstream transcriptional target genes [ 38 ].…”

Section: Discussioncontrasting

confidence: 99%

Pioglitazone Effect on Glioma Stem Cell Lines: Really a Promising Drug Therapy for Glioblastoma?

et al. 2016

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Glioblastoma multiforme (GBM) represents one of the most frequent malignant brain tumors. Current therapies do not provide real solutions to this pathology. Their failure can be ascribed to a cell subpopulation with stem-like properties called glioma stem cells (GSCs). Therefore, new therapeutic strategies GSC-targeted are needed. PPARγ, a nuclear receptor involved in lipid metabolism, has already been indicated as a promising target for antineoplastic therapies. Recent studies have reported that synthetic PPARγ agonists, already in clinical use for the treatment of type II diabetes, exhibit antineoplastic effects in a wide range of malignant tumor cells, including glioma cells. We investigated the effect of the synthetic PPARγ agonist Pioglitazone on viability, proliferation, morphology, and differentiation in six GSC lines isolated from GBM patients. We also analyzed Pioglitazone-induced changes in transcriptional levels of Wnt/β catenin related genes. Results showed that response to Pioglitazone was heterogeneous inducing an evident decrease of cell viability and proliferation only in a subset of GSC lines. We did not find any sign of cell differentiation neither observing cell morphology nor analyzing the expression of stemness and differentiation markers. Moreover, Wnt/β signaling pathway was only mildly affected from a transcriptional point of view after Pioglitazone exposure.

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Section: Discussioncontrasting

confidence: 99%

Pioglitazone Effect on Glioma Stem Cell Lines: Really a Promising Drug Therapy for Glioblastoma?

et al. 2016

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“…PPARγ ligands impair gastric cancer cell proliferation in a dose‐dependent manner owing to the upregulation of p53 and downregulation of cyclin E1 and tumor burden in mice was reduced after the treatment with a PPARγ agonist rosiglitazone . Moreover, overexpression of PPARγ inhibits the metastatic potential of gastric cancer cells through attenuation of Wnt/β‐catenin signaling and TERT expression . Our results demonstrate that elevated expression of PPARγ is associated with better survival outcomes in renal and bladder cancers, but poor survival outcomes in glioma (Figs.…”

Section: Discussionmentioning

confidence: 60%

The pan‐cancer mutational landscape of the PPAR pathway reveals universal patterns of dysregulated metabolism and interactions with tumor immunity and hypoxia

Lai

2019

Annals of the New York Academy of Sciences

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Peroxisome proliferator‐activated receptors (PPARs) are a family of nuclear receptors that regulate lipid metabolism and bioenergetic demands within living systems. Consequently, aberrant expression of PPAR genes could predispose individuals to diseases, including cancer. PPAR signaling exerts pleiotropic functions in cancer, yet little is known about the interactions between genetic and transcriptional events of pathway genes in a pan‐cancer context. Employing multidimensional datasets of over 18,000 patients involving 21 cancers, we performed systematic characterization on copy number alteration and differential transcript expression of 74 PPAR pathway genes. We identified 18 genes demonstrating mutually exclusive patterns of loss‐ and gain‐of‐function phenotypes. These genes successfully predicted patient survival rates in bladder, renal, glioma, liver, and stomach/esophageal cancers. Dysregulated PPAR signaling in these cancers converged on common downstream pathways associated with multiple metabolic processes. Moreover, clinically relevant relationships between PPARs and hypoxia were observed, where hypoxia further aggravates disease phenotypes in tumor subtypes with aberrant PPAR signaling. In glioma samples, including astrocytoma and oligoastrocytoma, PPAR hyperactivation is associated with immunosuppression through increased regulatory T cell expression. Our analysis reveals underappreciated levels of diversity and conservation in PPAR genes that could lay the groundwork for therapeutic strategies targeting tumor metabolism, immunity, and hypoxia.

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“…PPARγ ligands impair gastric cancer cell proliferation in a dose-dependent manner due to the upregulation of p53 and downregulation of cyclin E1 and tumor burden in mice was reduced after treatment with a PPARγ agonist rosiglitazone (46). Moreover, overexpression of PPARγ inhibits the metastatic potential of gastric cancer cells through attenuation of Wnt/β-Catenin signaling and TERT expression (47). Our results demonstrate that elevated expression of PPARγ is associated with better survival outcomes in renal and bladder cancers, but poor survival outcomes in glioma ( Fig.…”

Section: Discussionmentioning

confidence: 99%

Pan-cancer mutational landscape of the PPAR pathway reveals universal patterns of dysregulated metabolism and interactions with tumor immunity and hypoxia

Lai

2019

Preprint

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Peroxisome proliferator-activated receptors (PPARs) are a family of nuclear receptors that regulate lipid metabolism and bioenergetic demands within living systems. Consequently, aberrant expression of PPAR genes could predispose individuals to diseases including cancer. PPAR signaling exerts pleiotropic functions in cancer, yet, little is known about the interactions between genetic and transcriptional events of pathway genes in a pan-cancer context. Employing multidimensional datasets of over 18,000 patients involving 21 cancers, we performed systematic characterization on copy number alteration and differential transcript expression of 74 PPAR pathway genes. We identified 18 putative driver candidates demonstrating mutually exclusive patterns of loss-and gain-of-function phenotypes. These driver genes successfully predicted patient survival rates in bladder, renal, glioma, liver and stomach/esophageal cancers. Dysregulated PPAR signaling in these cancers converged on common downstream pathways associated with multiple metabolic processes. Moreover, clinically-relevant relationships between PPARs and hypoxia were observed where hypoxia further aggravates disease phenotypes in tumor subtypes with aberrant PPAR signaling. In glioma samples, including astrocytoma and oligoastrocytoma, PPAR hyperactivation is associated with immunosuppression through increased regulatory T cell expression. Our analysis reveals underappreciated levels of diversity and conservation in PPAR genes that could lay the groundwork for therapeutic strategies targeting tumor metabolism, immunity and hypoxia. PPAR | genomic alterations | metabolism | hypoxia | tumor immunity | glioma | hepatocellular carcinoma | renal cancer | pan-cancerCorrespondence: alvina.lai@ndm.ox.ac.uk

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Constitutive expression of PPARγ inhibits proliferation and migration of gastric cancer cells and down-regulates Wnt/β-Catenin signaling pathway downstream target genes TERT and ENAH

Cited by 33 publications

References 47 publications

Pioglitazone Effect on Glioma Stem Cell Lines: Really a Promising Drug Therapy for Glioblastoma?

Pioglitazone Effect on Glioma Stem Cell Lines: Really a Promising Drug Therapy for Glioblastoma?

The pan‐cancer mutational landscape of the PPAR pathway reveals universal patterns of dysregulated metabolism and interactions with tumor immunity and hypoxia

Pan-cancer mutational landscape of the PPAR pathway reveals universal patterns of dysregulated metabolism and interactions with tumor immunity and hypoxia

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