The MyD88+ phenotype is an adverse prognostic factor in epithelial ovarian cancer
Article
D’Adhemar, C., Spillane, C., Gallagher, M., Bates, M., Costello, K., Barry-O'Crowley, J., Haley, K., Kernan, N., Murphy, C., Smyth, P., O'Byrne, K., Pennington, S., Cooke, A., Ffrench, B., Martin, C., O'Donnell, D., Hennessy, B., Stordal, B., Finn, S., McCann, A., Gleeson, N., D'Arcy, T., Flood, B., O'Neill, L., Sheils, O., O'Toole, S. and O'Leary, J. 2014. The MyD88+ phenotype is an adverse prognostic factor in epithelial ovarian cancer. PLoS ONE. 9 (6), pp. 1-15. https://doi.org/10.1371/journal.pone.0100816
Type | Article |
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Title | The MyD88+ phenotype is an adverse prognostic factor in epithelial ovarian cancer |
Authors | D’Adhemar, C., Spillane, C., Gallagher, M., Bates, M., Costello, K., Barry-O'Crowley, J., Haley, K., Kernan, N., Murphy, C., Smyth, P., O'Byrne, K., Pennington, S., Cooke, A., Ffrench, B., Martin, C., O'Donnell, D., Hennessy, B., Stordal, B., Finn, S., McCann, A., Gleeson, N., D'Arcy, T., Flood, B., O'Neill, L., Sheils, O., O'Toole, S. and O'Leary, J. |
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. |
Research Group | Biomarkers for Cancer group |
Publisher | Public Library of Science |
Journal | PLoS ONE |
ISSN | |
Electronic | 1932-6203 |
Publication dates | |
30 Jun 2014 | |
Publication process dates | |
Deposited | 28 Apr 2015 |
Accepted | 30 May 2014 |
Output status | Published |
Publisher's version | License |
Copyright Statement | Copyright: © 2014 d’Adhemar et al. 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. |
Additional information | 17 Sep 2014: The PLOS ONE Staff (2014) Correction: The MyD88+ Phenotype Is an Adverse Prognostic Factor in Epithelial Ovarian Cancer. PLOS ONE 9(9): e108833. https://doi.org/10.1371/journal.pone.0108833 |
Digital Object Identifier (DOI) | https://doi.org/10.1371/journal.pone.0100816 |
PubMed ID | 24977712 |
PubMed Central ID | 4076208 |
Web of Science identifier | WOS:000338506400042 |
Language | English |
https://repository.mdx.ac.uk/item/85298
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