The MyD88+ phenotype is an adverse prognostic factor in epithelial ovarian cancer.

Hdl Handle:
http://hdl.handle.net/10147/559447
Title:
The MyD88+ phenotype is an adverse prognostic factor in epithelial ovarian cancer.
Authors:
d'Adhemar, Charles J; Spillane, Cathy D; Gallagher, Michael F; Bates, Mark; Costello, Katie M; Barry-O'Crowley, Jacqui; Haley, Kathryn; Kernan, Niamh; Murphy, Ciara; Smyth, Paul C; O'Byrne, Ken; Pennington, Stephen; Cooke, Aoife A; Ffrench, Brendan; Martin, Cara M; O'Donnell, Dearbhaile; Hennessy, Bryan; Stordal, Britta; Finn, Stephen; McCann, Amanda; Gleeson, Noreen; D'Arcy, Tom; Flood, Brian; O'Neill, Luke A J; Sheils, Orla; O'Toole, Sharon; O'Leary, John J
Citation:
The MyD88+ phenotype is an adverse prognostic factor in epithelial ovarian cancer. 2014, 9 (6):e100816 PLoS ONE
Journal:
PloS one
Issue Date:
2014
URI:
http://hdl.handle.net/10147/559447
DOI:
10.1371/journal.pone.0100816
PubMed ID:
24977712
Abstract:
The prognosis of epithelial ovarian cancer is poor in part due to the high frequency of chemoresistance. Recent evidence points to the Toll-like receptor-4 (TLR4), and particularly its adaptor protein MyD88, as one potential mediator of this resistance. This study aims to provide further evidence that MyD88 positive cancer cells are clinically significant, stem-like and reproducibly detectable for the purposes of prognostic stratification. Expression of TLR4 and MyD88 was assessed immunohistochemically in 198 paraffin-embedded ovarian tissues and in an embryonal carcinoma model of cancer stemness. In parallel, expression of TLR4 and MyD88 mRNA and regulatory microRNAs (miR-21 and miR-146a) was assessed, as well as in a series of chemosensitive and resistant cancer cells lines. Functional analysis of the pathway was assessed in chemoresistant SKOV-3 ovarian cancer cells. TLR4 and MyD88 expression can be reproducibly assessed via immunohistochemistry using a semi-quantitative scoring system. TLR4 expression was present in all ovarian epithelium (normal and neoplastic), whereas MyD88 was restricted to neoplastic cells, independent of tumour grade and associated with reduced progression-free and overall survival, in an immunohistological specific subset of serous carcinomas, p<0.05. MiR-21 and miR-146a expression was significantly increased in MyD88 negative cancers (p<0.05), indicating their participation in regulation. Significant alterations in MyD88 mRNA expression were observed between chemosensitive and chemoresistant cells and tissue. Knockdown of TLR4 in SKOV-3 ovarian cells recovered chemosensitivity. Knockdown of MyD88 alone did not. MyD88 expression was down-regulated in differentiated embryonal carcinoma (NTera2) cells, supporting the MyD88+ cancer stem cell hypothesis. Our findings demonstrate that expression of MyD88 is associated with significantly reduced patient survival and altered microRNA levels and suggest an intact/functioning TLR4/MyD88 pathway is required for acquisition of the chemoresistant phenotype. Ex vivo manipulation of ovarian cancer stem cell (CSC) differentiation can decrease MyD88 expression, providing a potentially valuable CSC model for ovarian cancer.
Item Type:
Article
Language:
en
MeSH:
Aged; Antineoplastic Agents, Phytogenic; Cell Line, Tumor; Cystadenocarcinoma, Serous; Drug Resistance, Neoplasm; Female; Gene Expression Regulation, Neoplastic; Genotype; Humans; Immunohistochemistry; MicroRNAs; Middle Aged; Myeloid Differentiation Factor 88; Neoplasms, Glandular and Epithelial; Neoplastic Stem Cells; Ovarian Neoplasms; Paclitaxel; Phenotype; Prognosis; RNA, Small Interfering; Signal Transduction; Survival Analysis; Toll-Like Receptor 4
ISSN:
1932-6203
Sponsors:
Funding: This work was supported by Cancer Research Ireland (grant reference number ICS CRP09OLE), the Meath foundation, The Royal City of Dublin Hospital Trust, BDI-2 (10/CE/B1821), the Emer Casey foundation, the Irish Cancer Society, and a Marie Curie European Union grant. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Full metadata record

DC FieldValue Language
dc.contributor.authord'Adhemar, Charles Jen
dc.contributor.authorSpillane, Cathy Den
dc.contributor.authorGallagher, Michael Fen
dc.contributor.authorBates, Marken
dc.contributor.authorCostello, Katie Men
dc.contributor.authorBarry-O'Crowley, Jacquien
dc.contributor.authorHaley, Kathrynen
dc.contributor.authorKernan, Niamhen
dc.contributor.authorMurphy, Ciaraen
dc.contributor.authorSmyth, Paul Cen
dc.contributor.authorO'Byrne, Kenen
dc.contributor.authorPennington, Stephenen
dc.contributor.authorCooke, Aoife Aen
dc.contributor.authorFfrench, Brendanen
dc.contributor.authorMartin, Cara Men
dc.contributor.authorO'Donnell, Dearbhaileen
dc.contributor.authorHennessy, Bryanen
dc.contributor.authorStordal, Brittaen
dc.contributor.authorFinn, Stephenen
dc.contributor.authorMcCann, Amandaen
dc.contributor.authorGleeson, Noreenen
dc.contributor.authorD'Arcy, Tomen
dc.contributor.authorFlood, Brianen
dc.contributor.authorO'Neill, Luke A Jen
dc.contributor.authorSheils, Orlaen
dc.contributor.authorO'Toole, Sharonen
dc.contributor.authorO'Leary, John Jen
dc.date.accessioned2015-07-10T10:44:47Zen
dc.date.available2015-07-10T10:44:47Zen
dc.date.issued2014en
dc.identifier.citationThe MyD88+ phenotype is an adverse prognostic factor in epithelial ovarian cancer. 2014, 9 (6):e100816 PLoS ONEen
dc.identifier.issn1932-6203en
dc.identifier.pmid24977712en
dc.identifier.doi10.1371/journal.pone.0100816en
dc.identifier.urihttp://hdl.handle.net/10147/559447en
dc.description.abstractThe prognosis of epithelial ovarian cancer is poor in part due to the high frequency of chemoresistance. Recent evidence points to the Toll-like receptor-4 (TLR4), and particularly its adaptor protein MyD88, as one potential mediator of this resistance. This study aims to provide further evidence that MyD88 positive cancer cells are clinically significant, stem-like and reproducibly detectable for the purposes of prognostic stratification. Expression of TLR4 and MyD88 was assessed immunohistochemically in 198 paraffin-embedded ovarian tissues and in an embryonal carcinoma model of cancer stemness. In parallel, expression of TLR4 and MyD88 mRNA and regulatory microRNAs (miR-21 and miR-146a) was assessed, as well as in a series of chemosensitive and resistant cancer cells lines. Functional analysis of the pathway was assessed in chemoresistant SKOV-3 ovarian cancer cells. TLR4 and MyD88 expression can be reproducibly assessed via immunohistochemistry using a semi-quantitative scoring system. TLR4 expression was present in all ovarian epithelium (normal and neoplastic), whereas MyD88 was restricted to neoplastic cells, independent of tumour grade and associated with reduced progression-free and overall survival, in an immunohistological specific subset of serous carcinomas, p<0.05. MiR-21 and miR-146a expression was significantly increased in MyD88 negative cancers (p<0.05), indicating their participation in regulation. Significant alterations in MyD88 mRNA expression were observed between chemosensitive and chemoresistant cells and tissue. Knockdown of TLR4 in SKOV-3 ovarian cells recovered chemosensitivity. Knockdown of MyD88 alone did not. MyD88 expression was down-regulated in differentiated embryonal carcinoma (NTera2) cells, supporting the MyD88+ cancer stem cell hypothesis. Our findings demonstrate that expression of MyD88 is associated with significantly reduced patient survival and altered microRNA levels and suggest an intact/functioning TLR4/MyD88 pathway is required for acquisition of the chemoresistant phenotype. Ex vivo manipulation of ovarian cancer stem cell (CSC) differentiation can decrease MyD88 expression, providing a potentially valuable CSC model for ovarian cancer.en
dc.description.sponsorshipFunding: This work was supported by Cancer Research Ireland (grant reference number ICS CRP09OLE), the Meath foundation, The Royal City of Dublin Hospital Trust, BDI-2 (10/CE/B1821), the Emer Casey foundation, the Irish Cancer Society, and a Marie Curie European Union grant. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.en
dc.language.isoenen
dc.rightsArchived with thanks to PloS oneen
dc.subject.meshAgeden
dc.subject.meshAntineoplastic Agents, Phytogenicen
dc.subject.meshCell Line, Tumoren
dc.subject.meshCystadenocarcinoma, Serousen
dc.subject.meshDrug Resistance, Neoplasmen
dc.subject.meshFemaleen
dc.subject.meshGene Expression Regulation, Neoplasticen
dc.subject.meshGenotypeen
dc.subject.meshHumansen
dc.subject.meshImmunohistochemistryen
dc.subject.meshMicroRNAsen
dc.subject.meshMiddle Ageden
dc.subject.meshMyeloid Differentiation Factor 88en
dc.subject.meshNeoplasms, Glandular and Epithelialen
dc.subject.meshNeoplastic Stem Cellsen
dc.subject.meshOvarian Neoplasmsen
dc.subject.meshPaclitaxelen
dc.subject.meshPhenotypeen
dc.subject.meshPrognosisen
dc.subject.meshRNA, Small Interferingen
dc.subject.meshSignal Transductionen
dc.subject.meshSurvival Analysisen
dc.subject.meshToll-Like Receptor 4en
dc.titleThe MyD88+ phenotype is an adverse prognostic factor in epithelial ovarian cancer.en
dc.typeArticleen
dc.identifier.journalPloS oneen
dc.description.fundingOtheren
dc.description.provinceLeinsteren
dc.description.peer-reviewpeer-reviewen

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