The MyD88+ phenotype is an adverse prognostic factor in epithelial ovarian cancer.
Authorsd'Adhemar, Charles J
Spillane, Cathy D
Gallagher, Michael F
Costello, Katie M
Smyth, Paul C
Cooke, Aoife A
Martin, Cara M
O'Neill, Luke A J
O'Leary, John J
Antineoplastic Agents, Phytogenic
Cell Line, Tumor
Drug Resistance, Neoplasm
Gene Expression Regulation, Neoplastic
Myeloid Differentiation Factor 88
Neoplasms, Glandular and Epithelial
Neoplastic Stem Cells
RNA, Small Interfering
Toll-Like Receptor 4
MetadataShow full item record
CitationThe MyD88+ phenotype is an adverse prognostic factor in epithelial ovarian cancer. 2014, 9 (6):e100816 PLoS ONE
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.
SponsorsFunding: 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.
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