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

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. (2014) The MyD88+ phenotype is an adverse prognostic factor in epithelial ovarian cancer. PLoS ONE, 9(6), e100816.

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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.

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ID Code: 78360
Item Type: Journal Article
Refereed: Yes
Keywords: messenger RNA, microRNA 146a, microRNA 21, myeloid differentiation factor 88, paraffin, toll like receptor 4, adult, adverse outcome, article, cancer grading, cancer prognosis, cancer resistance, cancer survival, chemosensitivity, controlled study, down regulation, embryo, embryonal carcinoma, female, gene expression, gene silencing, human, human tissue, immunohistochemistry, major clinical study, myd88 gene, ovarian cancer cell line, ovary carcinoma, overall survival, phenotype, progression free survival, protein function, survival rate, survival time, TLR4 gene
DOI: 10.1371/journal.pone.0100816
ISSN: 1932-6203
Subjects: Australian and New Zealand Standard Research Classification > MEDICAL AND HEALTH SCIENCES (110000) > ONCOLOGY AND CARCINOGENESIS (111200)
Divisions: Current > Schools > School of Biomedical Sciences
Current > QUT Faculties and Divisions > Faculty of Health
Current > Institutes > Institute of Health and Biomedical Innovation
Copyright Owner: Copyright 2014 d’Adhemar et al.
Copyright Statement: This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits
unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Deposited On: 03 Nov 2014 23:13
Last Modified: 04 Nov 2014 20:57

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