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Epigenetics override pro-inflammatory PTGS transcriptomic signature towards selective hyperactivation of PGE2 in colorectal cancer.

ABSTRACT: Misregulation of the PTGS (prostaglandin endoperoxide synthase, also known as cyclooxygenase or COX) pathway may lead to the accumulation of pro-inflammatory signals, which constitutes a hallmark of cancer. To get insight into the role of this signaling pathway in colorectal cancer (CRC), we have characterized the transcriptional and epigenetic landscapes of the PTGS pathway genes in normal and cancer cells.Data from four independent series of CRC patients (502 tumors including adenomas and carcinomas and 222 adjacent normal tissues) and two series of colon mucosae from 69 healthy donors have been included in the study. Gene expression was analyzed by real-time PCR and Affymetrix U219 arrays. DNA methylation was analyzed by bisulfite sequencing, dissociation curves, and HumanMethylation450K arrays. Most CRC patients show selective transcriptional deregulation of the enzymes involved in the synthesis of prostanoids and their receptors in both tumor and its adjacent mucosa. DNA methylation alterations exclusively affect the tumor tissue (both adenomas and carcinomas), redirecting the transcriptional deregulation to activation of prostaglandin E2 (PGE2) function and blockade of other biologically active prostaglandins. In particular, PTGIS, PTGER3, PTGFR, and AKR1B1 were hypermethylated in more than 40 % of all analyzed tumors.The transcriptional and epigenetic profiling of the PTGS pathway provides important clues on the biology of the tumor and its microenvironment. This analysis renders candidate markers with potential clinical applicability in risk assessment and early diagnosis and for the design of new therapeutic strategies.

SUBMITTER: Cebola I

PROVIDER: S-EPMC4512023 | biostudies-literature | 2015

REPOSITORIES: biostudies-literature

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Epigenetics override pro-inflammatory PTGS transcriptomic signature towards selective hyperactivation of PGE2 in colorectal cancer.

Cebola Inês I Custodio Joaquin J Muñoz Mar M Díez-Villanueva Anna A Paré Laia L Prieto Patricia P Aussó Susanna S Coll-Mulet Llorenç L Boscá Lisardo L Moreno Victor V Peinado Miguel A MA

Clinical epigenetics 20150724

<h4>Background</h4>Misregulation of the PTGS (prostaglandin endoperoxide synthase, also known as cyclooxygenase or COX) pathway may lead to the accumulation of pro-inflammatory signals, which constitutes a hallmark of cancer. To get insight into the role of this signaling pathway in colorectal cancer (CRC), we have characterized the transcriptional and epigenetic landscapes of the PTGS pathway genes in normal and cancer cells.<h4>Results</h4>Data from four independent series of CRC patients (502 ...[more]

PMID: 26207152

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Project description:Prostaglandin E2 (PGE2) is involved in numerous physiological and pathological processes of the kidney via its four receptors. A previous study has suggested that a defect in the PGE2 receptor 1 (EP1) gene markedly suppressed the transforming growth factor??1 (TGF??1)?induced mesangial cell (MC) proliferation and extracellular matrix aggregation. Therefore, the present study aimed to adopt a pharmacological method of specifically suppressing or activating the EP1 receptor to further verify and demonstrate these results. The EP1 receptor antagonist SC?19220 and EP1 receptor agonist 17?phenyl?trinor?PGE2 ethyl amide (17?pt?PGE2) were selectively used to treat five?sixths nephrectomy renal fibrosis model mice and TGF??1?stimulated MCs. An Alpha screen PGE2 assay kit, flow cytometry, western blotting and immunohistochemical techniques were adopted to perform in vivo and in vitro experiments. The present results suggested that compared with the control group, the selective EP1 receptor antagonist SC?19220 improved renal function, markedly reduced the plasma blood urea nitrogen and creatinine levels (P<0.05) and alleviated glomerulosclerosis (P<0.05). By contrast, the EP1 receptor agonist 17?pt?PGE2 aggravated renal dysfunction and glomerulosclerosis (P<0.05). To verify the renal protection mechanisms mediated by suppression of the EP1 receptor, the expression levels of endoplasmic reticulum stress (ERS)?related proteins, including chaperone glucose?regulated protein 78 (GRP78), transient receptor potential channel 1 (TRPC1) and protein kinase R?like endoplasmic reticulum kinase (PERK), were further evaluated histologically. The expression of GRP78, TRPC1 and PERK in the antagonist treatment group were markedly downregulated (P<0.05), whereas those in the agonist treatment group were upregulated (P<0.05). The present in vitro experiments demonstrated that, compared with the control group, the EP1 receptor antagonist suppressed the expression of GRP78, TRPC1 and PERK (P<0.05), reduced the production of PGE2 (P<0.05) and decreased the MC apoptosis rate (P<0.05), thus alleviating TGF??1?stimulated MC injury. Consequently, consistent with previous results, selectively antagonizing the EP1 receptor improved renal function and mitigated glomerulosclerosis, and its potential mechanism might be associated with the suppression of ERS.

Dataset Information

Epigenetics override pro-inflammatory PTGS transcriptomic signature towards selective hyperactivation of PGE2 in colorectal cancer.

Publications

Epigenetics override pro-inflammatory PTGS transcriptomic signature towards selective hyperactivation of PGE2 in colorectal cancer.

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