Type

Journal Article

Authors

John J O'Leary
Orla Sheils
Brian Flood
Tom D'Arcy
Amanda McCann
Stephen Finn
Britta Stordal
Bryan Hennessy
Dearbhaile O'Donnell
Cara M Martin
and 18 others

Subjects

Biochemistry

Topics
prognosis mirn146 microrna human myeloid differentiation factor 88 myd88 protein human toll like receptor 4 paclitaxel carcinoma cells humans tlr4 protein human ovarian neoplasms drug effects high frequency antineoplastic agents phytogenic female micrornas antagonists inhibitors neoplasms glandular and epithelial predictive biomarkers functional analysis signal transduction genetics genotype computer assisted language learning rna small interfering cancer cells pathology metabolism diagnosis survival analysis mirn21 microrna human health drug therapy aged ovarian cancer phenotype cancer cancer stem cells neoplastic stem cells stem cell differentiation middle aged gene expression regulation neoplastic drug resistance neoplasm mortality cystadenocarcinoma serous pharmacology immunohistochemistry mrna expression cell line tumor

The MyD88+ Phenotype Is an Adverse Prognostic Factor in Epithelial Ovarian Cancer. (2014)

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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Full list of authors on original publication

John J O'Leary, Orla Sheils, Brian Flood, Tom D'Arcy, Amanda McCann, Stephen Finn, Britta Stordal, Bryan Hennessy, Dearbhaile O'Donnell, Cara M Martin and 18 others

Experts in our system

1
John O'Leary
Trinity College Dublin
Total Publications: 93
 
2
Orla Sheils
Trinity College Dublin
Total Publications: 55
 
3
Tom D'Arcy
Dublin City University
Total Publications: 13
 
4
Amanda McCann
University College Dublin
Total Publications: 41
 
5
Stephen P Finn
Trinity College Dublin
Total Publications: 60
 
6
Britta Kristina Stordal
Trinity College Dublin
Total Publications: 29
 
7
Bryan T Hennessy
Royal College of Surgeons in Ireland
Total Publications: 33
 
8
Dearbhaile O'Donnell
Trinity College Dublin
 
9
Cara Martin
Trinity College Dublin
Total Publications: 49