The MyD88+ Phenotype Is an Adverse Prognostic Factor in Epithelial Ovarian Cancer

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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)
  • Publisher: Public Library of Science
  • Journal: PLoS ONE, volume 9, issue 6 (eissn: 1932-6203)
  • Related identifiers: doi: 10.1371/journal.pone.0100816, pmc: PMC4076208
  • Subject: Computational Biology | Predictive Biomarkers | Research Article | Biology and Life Sciences | Molecular Cell Biology | RNA | Anatomy | Health | Genome Expression Analysis | Functional Genomics | computer-assisted language learning | Nucleic Acids | Carcinoma cells | Cell Biology | Genetics | Histology | Autoimmunity | Genome Analysis | Biochemistry | Genomics | Cancer | Cancer stem cells | Transcriptome Analysis | Immunology

PUBLISHED 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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