The MyD88+ phenotype is an adverse prognostic factor in epithelial ovarian cancer.
Authors
d'Adhemar, Charles JSpillane, 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
Issue Date
2014MeSH
AgedAntineoplastic 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
Metadata
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The MyD88+ phenotype is an adverse prognostic factor in epithelial ovarian cancer. 2014, 9 (6):e100816 PLoS ONEJournal
PloS oneDOI
10.1371/journal.pone.0100816PubMed ID
24977712Abstract
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
ArticleLanguage
enISSN
1932-6203Sponsors
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.ae974a485f413a2113503eed53cd6c53
10.1371/journal.pone.0100816
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