Prostacyclin synthase expression and epigenetic regulation in nonsmall cell lung cancer.

Hdl Handle:
http://hdl.handle.net/10147/207834
Title:
Prostacyclin synthase expression and epigenetic regulation in nonsmall cell lung cancer.
Authors:
Cathcart, Mary-Clare; Gray, Steven G; Baird, Anne-Marie; Boyle, Elaine; Gately, Kathy; Kay, Elaine; Cummins, Robert; Pidgeon, Graham P; O'Byrne, Kenneth J
Affiliation:
Department of Clinical Medicine, Translational Cancer Research Group, Institute, of Molecular Medicine, Trinity Centre for Health Sciences, St. James' Hospital,, Dublin, Ireland.
Citation:
Cancer. 2011 Nov 15;117(22):5121-32. doi: 10.1002/cncr.26168. Epub 2011 Apr 26.
Journal:
Cancer
Issue Date:
1-Feb-2012
URI:
http://hdl.handle.net/10147/207834
DOI:
10.1002/cncr.26168
PubMed ID:
21523772
Abstract:
BACKGROUND: Prostacyclin synthase (PGIS) metabolizes prostaglandin H(2), into prostacyclin. This study aimed to determine the expression profile of PGIS in nonsmall cell lung cancer (NSCLC) and examine potential mechanisms involved in PGIS regulation. METHODS: PGIS expression was examined in human NSCLC and matched controls by reverse transcriptase polymerase chain reaction (RT-PCR), Western analysis, and immunohistochemistry. A 204-patient NSCLC tissue microarray was stained for PGIS and cyclooxygenase 2 (COX2) expression. Staining intensity was correlated with clinical parameters. Epigenetic mechanisms underpinning PGIS promoter expression were examined using RT-PCR, methylation-specific PCR, and chromatin immunoprecipitation analysis. RESULTS: PGIS expression was reduced/absent in human NSCLC protein samples (P < .0001), but not mRNA relative to matched controls. PGIS tissue expression was higher in squamous cell carcinoma (P = .004) and in male patients (P < .05). No significant correlation of PGIS or COX2 expression with overall patient survival was observed, although COX2 was prognostic for short-term (2-year) survival (P < .001). PGIS mRNA expression was regulated by DNA CpG methylation and histone acetylation in NSCLC cell lines, with chromatin remodeling taking place directly at the PGIS gene. PGIS mRNA expression was increased by both demethylation agents and histone deacetylase inhibitors. Protein levels were unaffected by demethylation agents, whereas PGIS protein stability was negatively affected by histone deacetylase inhibitors. CONCLUSIONS: PGIS protein expression is reduced in NSCLC, and does not correlate with overall patient survival. PGIS expression is regulated through epigenetic mechanisms. Differences in expression patterns between mRNA and protein levels suggest that PGIS expression and protein stability are regulated post-translationally. PGIS protein stability may have an important therapeutic role in NSCLC.
Language:
eng
MeSH:
Adenocarcinoma/enzymology/genetics; Adult; Aged; Carcinoma, Non-Small-Cell Lung/*enzymology/*genetics; Carcinoma, Squamous Cell/enzymology/genetics; Cyclooxygenase 2/metabolism; Cytochrome P-450 Enzyme System/*metabolism; *Epigenesis, Genetic; Female; Gene Expression Regulation, Enzymologic; Gene Expression Regulation, Neoplastic; Humans; Intramolecular Oxidoreductases/*metabolism; Lung Neoplasms/*enzymology/*genetics; Male; Middle Aged; Prognosis
ISSN:
1097-0142 (Electronic); 0008-543X (Linking)

Full metadata record

DC FieldValue Language
dc.contributor.authorCathcart, Mary-Clareen_GB
dc.contributor.authorGray, Steven Gen_GB
dc.contributor.authorBaird, Anne-Marieen_GB
dc.contributor.authorBoyle, Elaineen_GB
dc.contributor.authorGately, Kathyen_GB
dc.contributor.authorKay, Elaineen_GB
dc.contributor.authorCummins, Roberten_GB
dc.contributor.authorPidgeon, Graham Pen_GB
dc.contributor.authorO'Byrne, Kenneth Jen_GB
dc.date.accessioned2012-02-01T10:46:01Z-
dc.date.available2012-02-01T10:46:01Z-
dc.date.issued2012-02-01T10:46:01Z-
dc.identifier.citationCancer. 2011 Nov 15;117(22):5121-32. doi: 10.1002/cncr.26168. Epub 2011 Apr 26.en_GB
dc.identifier.issn1097-0142 (Electronic)en_GB
dc.identifier.issn0008-543X (Linking)en_GB
dc.identifier.pmid21523772en_GB
dc.identifier.doi10.1002/cncr.26168en_GB
dc.identifier.urihttp://hdl.handle.net/10147/207834-
dc.description.abstractBACKGROUND: Prostacyclin synthase (PGIS) metabolizes prostaglandin H(2), into prostacyclin. This study aimed to determine the expression profile of PGIS in nonsmall cell lung cancer (NSCLC) and examine potential mechanisms involved in PGIS regulation. METHODS: PGIS expression was examined in human NSCLC and matched controls by reverse transcriptase polymerase chain reaction (RT-PCR), Western analysis, and immunohistochemistry. A 204-patient NSCLC tissue microarray was stained for PGIS and cyclooxygenase 2 (COX2) expression. Staining intensity was correlated with clinical parameters. Epigenetic mechanisms underpinning PGIS promoter expression were examined using RT-PCR, methylation-specific PCR, and chromatin immunoprecipitation analysis. RESULTS: PGIS expression was reduced/absent in human NSCLC protein samples (P < .0001), but not mRNA relative to matched controls. PGIS tissue expression was higher in squamous cell carcinoma (P = .004) and in male patients (P < .05). No significant correlation of PGIS or COX2 expression with overall patient survival was observed, although COX2 was prognostic for short-term (2-year) survival (P < .001). PGIS mRNA expression was regulated by DNA CpG methylation and histone acetylation in NSCLC cell lines, with chromatin remodeling taking place directly at the PGIS gene. PGIS mRNA expression was increased by both demethylation agents and histone deacetylase inhibitors. Protein levels were unaffected by demethylation agents, whereas PGIS protein stability was negatively affected by histone deacetylase inhibitors. CONCLUSIONS: PGIS protein expression is reduced in NSCLC, and does not correlate with overall patient survival. PGIS expression is regulated through epigenetic mechanisms. Differences in expression patterns between mRNA and protein levels suggest that PGIS expression and protein stability are regulated post-translationally. PGIS protein stability may have an important therapeutic role in NSCLC.en_GB
dc.language.isoengen_GB
dc.subject.meshAdenocarcinoma/enzymology/geneticsen_GB
dc.subject.meshAdulten_GB
dc.subject.meshAgeden_GB
dc.subject.meshCarcinoma, Non-Small-Cell Lung/*enzymology/*geneticsen_GB
dc.subject.meshCarcinoma, Squamous Cell/enzymology/geneticsen_GB
dc.subject.meshCyclooxygenase 2/metabolismen_GB
dc.subject.meshCytochrome P-450 Enzyme System/*metabolismen_GB
dc.subject.mesh*Epigenesis, Geneticen_GB
dc.subject.meshFemaleen_GB
dc.subject.meshGene Expression Regulation, Enzymologicen_GB
dc.subject.meshGene Expression Regulation, Neoplasticen_GB
dc.subject.meshHumansen_GB
dc.subject.meshIntramolecular Oxidoreductases/*metabolismen_GB
dc.subject.meshLung Neoplasms/*enzymology/*geneticsen_GB
dc.subject.meshMaleen_GB
dc.subject.meshMiddle Ageden_GB
dc.subject.meshPrognosisen_GB
dc.titleProstacyclin synthase expression and epigenetic regulation in nonsmall cell lung cancer.en_GB
dc.contributor.departmentDepartment of Clinical Medicine, Translational Cancer Research Group, Institute, of Molecular Medicine, Trinity Centre for Health Sciences, St. James' Hospital,, Dublin, Ireland.en_GB
dc.identifier.journalCanceren_GB
dc.description.provinceLeinster-

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