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PLoS One ; 9(6): e100816, 2014.
Article in English | MEDLINE | ID: mdl-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.


Subject(s)
Cystadenocarcinoma, Serous/genetics , Drug Resistance, Neoplasm/genetics , Gene Expression Regulation, Neoplastic , Myeloid Differentiation Factor 88/genetics , Neoplasms, Glandular and Epithelial/genetics , Ovarian Neoplasms/genetics , Toll-Like Receptor 4/genetics , Aged , Antineoplastic Agents, Phytogenic/pharmacology , Carcinoma, Ovarian Epithelial , Cell Line, Tumor , Cystadenocarcinoma, Serous/diagnosis , Cystadenocarcinoma, Serous/drug therapy , Cystadenocarcinoma, Serous/mortality , Female , Genotype , Humans , Immunohistochemistry , MicroRNAs/genetics , MicroRNAs/metabolism , Middle Aged , Myeloid Differentiation Factor 88/metabolism , Neoplasms, Glandular and Epithelial/diagnosis , Neoplasms, Glandular and Epithelial/drug therapy , Neoplasms, Glandular and Epithelial/mortality , Neoplastic Stem Cells/drug effects , Neoplastic Stem Cells/metabolism , Neoplastic Stem Cells/pathology , Ovarian Neoplasms/diagnosis , Ovarian Neoplasms/drug therapy , Ovarian Neoplasms/mortality , Paclitaxel/pharmacology , Phenotype , Prognosis , RNA, Small Interfering/genetics , RNA, Small Interfering/metabolism , Signal Transduction , Survival Analysis , Toll-Like Receptor 4/antagonists & inhibitors , Toll-Like Receptor 4/metabolism
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